Irak degraders and uses thereof

ABSTRACT

The present invention provides compounds, compositions thereof, and methods of using the same.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Appl. No.62/949,320, filed Dec. 17, 2019, U.S. Provisional Appl. No. 63/041,273,filed Jun. 19, 2020, and U.S. Provisional Appl. No. 63/123,147, filedDec. 9, 2020, the content of each of which is herein incorporated byreference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds and methods useful for themodulation of one or more interleukin-1 receptor-associated kinases(“IRAK”) via ubiquitination and/or degradation by compounds according tothe present invention. The invention also provides pharmaceuticallyacceptable compositions comprising compounds of the present inventionand methods of using said compositions in the treatment of variousdisorders.

BACKGROUND OF THE INVENTION

Ubiquitin-Proteasome Pathway (UPP) is a critical pathway that regulateskey regulator proteins and degrades misfolded or abnormal proteins. UPPis central to multiple cellular processes, and if defective orimbalanced, it leads to pathogenesis of a variety of diseases. Thecovalent attachment of ubiquitin to specific protein substrates isachieved through the action of E3 ubiquitin ligases.

There are over 600 E3 ubiquitin ligases which facilitate theubiquitination of different proteins in vivo, which can be divided intofour families: HECT-domain E3s, U-box E3s, monomeric RING E3s andmulti-subunit E3s. See generally Li et al. (PLOS One, 2008, 3, 1487)titled “Genome-wide and functional annotation of human E3 ubiquitinligases identifies MULAN, a mitochondrial E3 that regulates theorganelle's dynamics and signaling.”; Bemdsen et al. (Nat. Struct. Mol.Biol., 2014, 21, 301-307) titled “New insights into ubiquitin E3 ligasemechanism”; Deshaies et al. (Ann. Rev. Biochem., 2009, 78, 399-434)titled “RING domain E3 ubiquitin ligases.”; Spratt et al. (Biochem.2014, 458, 421-437) titled “RBR E3 ubiquitin ligases: new structures,new insights, new questions.”; and Wang et al. (Nat. Rev. Cancer., 2014,14, 233-347) titled “Roles of F-box proteins in cancer.”

UPP plays a key role in the degradation of short-lived and regulatoryproteins important in a variety of basic cellular processes, includingregulation of the cell cycle, modulation of cell surface receptors andion channels, and antigen presentation. The pathway has been implicatedin several forms of malignancy, in the pathogenesis of several geneticdiseases (including cystic fibrosis, Angelman's syndrome, and Liddlesyndrome), in immune surveillance/viral pathogenesis, and in thepathology of muscle wasting. Many diseases are associated with anabnormal UPP and negatively affect cell cycle and division, the cellularresponse to stress and to extracellular modulators, morphogenesis ofneuronal networks, modulation of cell surface receptors, ion channels,the secretory pathway, DNA repair and biogenesis of organelles.

Aberrations in the process have recently been implicated in thepathogenesis of several diseases, both inherited and acquired. Thesediseases fall into two major groups: (a) those that result from loss offunction with the resultant stabilization of certain proteins, and (b)those that result from gain of function, i.e. abnormal or accelerateddegradation of the protein target.

The UPP is used to induce selective protein degradation, including useof fusion proteins to artificially ubiquitinate target proteins andsynthetic small-molecule probes to induce proteasome-dependentdegradation. Bifunctional compounds composed of a target protein-bindingligand and an E3 ubiquitin ligase ligand, induced proteasome-mediateddegradation of selected proteins via their recruitment to E3 ubiquitinligase and subsequent ubiquitination. These drug-like molecules offerthe possibility of temporal control over protein expression. Suchcompounds are capable of inducing the inactivation of a protein ofinterest upon addition to cells or administration to an animal or human,and could be useful as biochemical reagents and lead to a new paradigmfor the treatment of diseases by removing pathogenic or oncogenicproteins (Crews C, Chemistry & Biology, 2010, 17(6):551-555; SchnneklothJS Jr., Chembiochem, 2005, 6(1): 40-46).

An ongoing need exists in the art for effective treatments for disease,especially hyperplasias and cancers, such as multiple myeloma. However,non-specific effects, and the inability to target and modulate certainclasses of proteins altogether, such as transcription factors, remain asobstacles to the development of effective anti-cancer agents. As such,small molecule therapeutic agents that leverage E3 ligase mediatedprotein degradation to target cancer-associated proteins such asinterleukin-1 receptor-associated kinases (“IRAK”) hold promise astherapeutic agents. Accordingly, there remains a need to find compoundsthat are IRAK degraders useful as therapeutic agents.

SUMMARY OF THE INVENTION

The present application relates novel bifunctional compounds, whichfunction to recruit IRAK kinases to E3 Ubiquitin Ligase for degradation,and methods of preparation and uses thereof. In particular, the presentdisclosure provides bifunctional compounds, which find utility asmodulators of targeted ubiquitination of IRAK kinases, which are thendegraded and/or otherwise inhibited by the bifunctional compounds asdescribed herein. Also provided are monovalent compounds, which findutility as inducers of targeted ubiquitination of IRAK kinases, whichare then degraded and/or otherwise inhibited by the monovalent compoundsas described herein. An advantage of the compounds provided herein isthat a broad range of pharmacological activities is possible, consistentwith the degradation/inhibition of IRAK kinases. In addition, thedescription provides methods of using an effective amount of thecompounds as described herein for the treatment or amelioration of adisease condition, such as cancer, e.g., multiple myeloma.

The present application further relates to targeted degradation of IRAKkinases through the use of bifunctional molecules, includingbifunctional molecules that link a degradation inducing moiety to aligand that binds IRAK kinases having the following general formula I:

or a pharmaceutically acceptable salt thereof, wherein each variable isas defined and described herein.

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are effective for themodulation of targeted ubiquitination. Such compounds have the formulaI-a:

or a pharmaceutically acceptable salt thereof, wherein each variable isas defined and described herein.

Compounds of the present invention, and pharmaceutically acceptablecompositions thereof, are useful for treating a variety of diseases,disorders or conditions, associated with regulation of signalingpathways implicating IRAK kinases. Such diseases, disorders, orconditions include those described herein.

Compounds provided by this invention are also useful for the study ofIRAK enzymes in biological and pathological phenomena; the study ofintracellular signal transduction pathways occurring in bodily tissues;and the comparative evaluation of new IRAK inhibitors or IRAK degradersor other regulators of kinases, signaling pathways, and cytokine levelsin vitro or in vivo.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description ofCertain Embodiments of the Invention

Compounds of the present invention, and compositions thereof, are usefulas degraders and/or inhibitors of one or more IRAK protein kinases. Insome embodiments, a provided compound degrades and/or inhibitsIRAK-1/2/3/4.

In certain embodiments, the present invention provides a compound offormula I:

or a pharmaceutically acceptable salt thereof, wherein:IRAK is an IRAK binding moiety capable of binding to one or more ofIRAK-1, -2, -3, or -4;L is a bivalent moiety that connects IRAK to DIM; andDIM is a degradation inducing moiety.

2. Compounds and Definitions

Compounds of the present invention include those described generallyherein, and are further illustrated by the classes, subclasses, andspecies disclosed herein. As used herein, the following definitionsshall apply unless otherwise indicated. For purposes of this invention,the chemical elements are identified in accordance with the PeriodicTable of the Elements, CAS version, Handbook of Chemistry and Physics,75^(th) Ed. Additionally, general principles of organic chemistry aredescribed in “Organic Chemistry”, Thomas Sorrell, University ScienceBooks, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th)Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001,the entire contents of which are hereby incorporated by reference.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1-6 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-5aliphatic carbon atoms. In other embodiments, aliphatic groups contain1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groupscontain 1-3 aliphatic carbon atoms, and in yet other embodiments,aliphatic groups contain 1-2 aliphatic carbon atoms. In someembodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refersto a monocyclic C₃-C₆ hydrocarbon that is completely saturated or thatcontains one or more units of unsaturation, but which is not aromatic,that has a single point of attachment to the rest of the molecule.Suitable aliphatic groups include, but are not limited to, linear orbranched, substituted or unsubstituted alkyl, alkenyl, alkynyl groupsand hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl.

As used herein, the term “bridged bicyclic” refers to any bicyclic ringsystem, i.e. carbocyclic or heterocyclic, saturated or partiallyunsaturated, having at least one bridge. As defined by IUPAC, a “bridge”is an unbranched chain of atoms or an atom or a valence bond connectingtwo bridgeheads, where a “bridgehead” is any skeletal atom of the ringsystem which is bonded to three or more skeletal atoms (excludinghydrogen). In some embodiments, a bridged bicyclic group has 7-12 ringmembers and 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Such bridged bicyclic groups are well known in theart and include those groups set forth below where each group isattached to the rest of the molecule at any substitutable carbon ornitrogen atom. Unless otherwise specified, a bridged bicyclic group isoptionally substituted with one or more substituents as set forth foraliphatic groups. Additionally or alternatively, any substitutablenitrogen of a bridged bicyclic group is optionally substituted.Exemplary bridged bicyclics include:

The term “lower alkyl” refers to a C₁₋₄ straight or branched alkylgroup. Exemplary lower alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, and tert-butyl.

The term “lower haloalkyl” refers to a C₁₋₄ straight or branched alkylgroup that is substituted with one or more halogen atoms.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quatemized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl). NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated,” as used herein, means that a moiety has one ormore units of unsaturation.

As used herein, the term “bivalent C₁₋₈ (or C₁₋₆) saturated orunsaturated, straight or branched, hydrocarbon chain”, refers tobivalent alkylene, alkenylene, and alkynylene chains that are straightor branched as defined herein.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “alkenylene” refers to a bivalent alkenyl group. A substitutedalkenylene chain is a polymethylene group containing at least one doublebond in which one or more hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

As used herein, the term “cyclopropylenyl” refers to a bivalentcyclopropyl group of the following structure:

The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic orbicyclic ring systems having a total of five to fourteen ring members,wherein at least one ring in the system is aromatic and wherein eachring in the system contains 3 to 7 ring members. The term “aryl” may beused interchangeably with the term “aryl ring.” In certain embodimentsof the present invention, “aryl” refers to an aromatic ring system whichincludes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl andthe like, which may bear one or more substituents. Also included withinthe scope of the term “aryl,” as it is used herein, is a group in whichan aromatic ring is fused to one or more non-aromatic rings, such asindanyl, phthalimidyl, naphthimidyl, phenanthridinyl, ortetrahydronaphthyl, and the like.

The terms “heteroaryl” and “heteroar-,” used alone or as part of alarger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer togroups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms;having 6, 10, or 14% electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. The term“heteroatom” refers to nitrogen, oxygen, or sulfur, and includes anyoxidized form of nitrogen or sulfur, and any quatemized form of a basicnitrogen. Heteroaryl groups include, without limitation, thienyl,furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and“heteroar-”, as used herein, also include groups in which aheteroaromatic ring is fused to one or more aryl, cycloaliphatic, orheterocyclyl rings, where the radical or point of attachment is on theheteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl,benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, 4H quinolizinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Aheteroaryl group may be mono- or bicyclic. The term “heteroaryl” may beused interchangeably with the terms “heteroaryl ring,” “heteroarylgroup,” or “heteroaromatic,” any of which terms include rings that areoptionally substituted. The term “heteroaralkyl” refers to an alkylgroup substituted by a heteroaryl, wherein the alkyl and heteroarylportions independently are optionally substituted.

As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclicradical,” and “heterocyclic ring” are used interchangeably and refer toa stable 5- to 7-membered monocyclic or 7-10-membered bicyclicheterocyclic moiety that is either saturated or partially unsaturated,and having, in addition to carbon atoms, one or more, preferably one tofour, heteroatoms, as defined above. When used in reference to a ringatom of a heterocycle, the term “nitrogen” includes a substitutednitrogen. As an example, in a saturated or partially unsaturated ringhaving 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, thenitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl). NH (as inpyrrolidinyl), or ⁺NR (as in N substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. Theterms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclicgroup,” “heterocyclic moiety,” and “heterocyclic radical,” are usedinterchangeably herein, and also include groups in which a heterocyclylring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings,such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, ortetrahydroquinolinyl. A heterocyclyl group may be mono- or bicyclic. Theterm “heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aryl or heteroarylmoieties, as herein defined.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted” means that oneor more hydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable,” as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and, in certainembodiments, their recovery, purification, and use for one or more ofthe purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘); —O(CH₂)₀₋₄R^(∘), —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph, which may besubstituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(∘); —CH═CHPh, which may be substituted with R^(∘);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(∘); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)R^(∘);—N(R^(∘))C(S)R^(∘); —(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂: —N(R^(∘))C(S)NR^(∘)₂; —(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘): N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃; —(CH₂)₀₋₄OC(O)R^(∘);—OC(O)(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄SC(O)R^(∘); —(CH₂)₀₋₄C(O)NR^(∘) ₂;—C(S)NR^(∘) ₂; —C(S)SR^(∘); —SC(S)SR^(∘), —(CH₂)₀₋₄OC(O)NR^(∘) ₂;—C(O)N(OR^(∘))R^(∘); —C(O)C(O)R^(∘); —C(O)CH₂C(O)R^(∘);—C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘); —(CH₂)₀₋₄S(O)₂R^(∘);—(CH₂)₀₋₄S(O)₂OR^(∘); —(CH₂)₀₋₄OS(O)₂R^(∘); —S(O)₂NR^(∘) ₂;—(CH₂)₀₋₄S(O)R^(∘); —N(R^(∘))S(O)₂NR^(∘) ₂; —N(R^(∘))S(O)₂R^(∘);—N(OR^(∘))R^(∘); —C(NH)NR^(∘) ₂; —P(O)₂R^(∘); —P(O)R^(∘) ₂; —OP(O)R^(∘)₂; —OP(O)(OR^(∘))₂; SiR^(∘) ₃; —(C₁₋₄ straight or branchedalkylene)O—N(R^(∘))₂; or —(C₁₋₄ straight or branchedalkylene)C(O)O—N(R^(∘))₂, wherein each R^(∘) may be substituted asdefined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(∘), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^(∘) (or the ring formed by takingtwo independent occurrences of R^(∘) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R^(●), -(haloR^(●)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(●), —(CH₂)₀₋₂CH(OR^(●))₂: —O(haloR^(●)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(●), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(●),—(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(●),—(CH₂)₀₋₂NR^(●) ₂, —NO₂, —SiR^(●) ₃, —OSiR^(●) ₃, —C(O)SR^(●)—(C₁₋₄straight or branched alkylene)C(O)OR^(●), or —SSR^(●) wherein each R^(●)is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R^(∘) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*. ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN, —C(O)OH,—C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein each R^(●) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†): wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN,—C(O)OH, —C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein eachR^(●) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

As used herein, the term “provided compound” refers to any genus,subgenus, and/or species set forth herein.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid ormalonic acid or by using other methods used in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzene sulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methane sulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate,propionate, stearate, succinate, sulfate, tartrate, thiocyanate,p-toluenesulfonate, undecanoate, valerate salts, and the like.

Salts derived from appropriate bases include alkali metal, alkalineearth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. Representative alkali oralkaline earth metal salts include sodium, lithium, potassium, calcium,magnesium, and the like. Further pharmaceutically acceptable saltsinclude, when appropriate, nontoxic ammonium, quaternary ammonium, andamine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and arylsulfonate.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the invention. Unless otherwise stated, all tautomeric forms of thecompounds of the invention are within the scope of the invention.Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention. Such compounds are useful, forexample, as analytical tools, as probes in biological assays, or astherapeutic agents in accordance with the present invention

As used herein, the term “inhibitor” is defined as a compound that bindsto and/or inhibits an IRAK kinase with measurable affinity. In certainembodiments, an inhibitor has an IC₅₀ and/or binding constant of lessthan about 50 μM, less than about 1 μM, less than about 500 nM, lessthan about 100 nM, less than about 10 nM, or less than about 1 nM.

As used herein, the term “degrader” is defined as a heterobifunctionalor monovalent compound that binds to and/or inhibits both an IRAK kinaseand an E3 ligase with measurable affinity resulting in theubiquitination and subsequent degradation of the IRAK kinase. In certainembodiments, a degrader has an DC₅₀ of less than about 50 μM, less thanabout 1 μM, less than about 500 nM, less than about 100 nM, less thanabout 10 nM, or less than about 1 nM. As used herein, the term“monovalent” refers to a degrader compound without an appended E3 ligasebinding moiety.

A compound of the present invention may be tethered to a detectablemoiety. It will be appreciated that such compounds are useful as imagingagents. One of ordinary skill in the art will recognize that adetectable moiety may be attached to a provided compound via a suitablesubstituent. As used herein, the term “suitable substituent” refers to amoiety that is capable of covalent attachment to a detectable moiety.Such moieties are well known to one of ordinary skill in the art andinclude groups containing, e.g., a carboxylate moiety, an amino moiety,a thiol moiety, or a hydroxyl moiety, to name but a few. It will beappreciated that such moieties may be directly attached to a providedcompound or via a tethering group, such as a bivalent saturated orunsaturated hydrocarbon chain. In some embodiments, such moieties may beattached via click chemistry. In some embodiments, such moieties may beattached via a 1,3-cycloaddition of an azide with an alkyne, optionallyin the presence of a copper catalyst. Methods of using click chemistryare known in the art and include those described by Rostovtsev et al.,Angew. Chem. Int. Ed. 2002, 41, 2596-99 and Sun et al., BioconjugateChem., 2006, 17, 52-57.

As used herein, the term “detectable moiety” is used interchangeablywith the term “label” and relates to any moiety capable of beingdetected, e.g., primary labels and secondary labels. Primary labels,such as radioisotopes (e.g., tritium, ³²P, ³³P, ³⁵S, or ¹⁴C), mass-tags,and fluorescent labels are signal generating reporter groups which canbe detected without further modifications. Detectable moieties alsoinclude luminescent and phosphorescent groups.

The term “secondary label” as used herein refers to moieties such asbiotin and various protein antigens that require the presence of asecond intermediate for production of a detectable signal. For biotin,the secondary intermediate may include streptavidin-enzyme conjugates.For antigen labels, secondary intermediates may include antibody-enzymeconjugates. Some fluorescent groups act as secondary labels because theytransfer energy to another group in the process of nonradiativefluorescent resonance energy transfer (FRET), and the second groupproduces the detected signal.

The terms “fluorescent label”, “fluorescent dye”, and “fluorophore” asused herein refer to moieties that absorb light energy at a definedexcitation wavelength and emit light energy at a different wavelength.Examples of fluorescent labels include, but are not limited to: AlexaFluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, AlexaFluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, AlexaFluor 660 and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL,BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530/550, BODIPY 558/568,BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY 630/650, BODIPY650/665), Carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), Cascade Blue,Cascade Yellow, Coumarin 343, Cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5),Dansyl, Dapoxyl, Dialkylaminocoumarin,4′,5′-Dichloro-2′,7′-dimethoxy-fluorescein, DM-NERF, Eosin, Erythrosin,Fluorescein, FAM, Hydroxycoumarin, IRDyes (IRD40, IRD 700, IRD 800),JOE, Lissamine rhodamine B, Marina Blue, Methoxycoumarin,Naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green514, Pacific Blue, PyMPO, Pyrene, Rhodamine B, Rhodamine 6G, RhodamineGreen, Rhodamine Red, Rhodol Green,2′,4′,5′,7′-Tetra-bromosulfone-fluorescein, Tetramethyl-rhodamine (TMR),Carboxytetramethylrhodamine (TAMRA), Texas Red, Texas Red-X.

The term “mass-tag” as used herein refers to any moiety that is capableof being uniquely detected by virtue of its mass using mass spectrometry(MS) detection techniques. Examples of mass-tags include electrophorerelease tags such asN-[3-[4′-[(p-Methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipecoticAcid, 4′-[2,3,5,6-Tetrafluoro-4-(pentafluorophenoxyl)]methylacetophenone, and their derivatives. The synthesis and utility of thesemass-tags is described in U.S. Pat. Nos. 4,650,750, 4,709,016,5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020, and 5,650,270.Other examples of mass-tags include, but are not limited to,nucleotides, dideoxynucleotides, oligonucleotides of varying length andbase composition, oligopeptides, oligosaccharides, and other syntheticpolymers of varying length and monomer composition. A large variety oforganic molecules, both neutral and charged (biomolecules or syntheticcompounds) of an appropriate mass range (100-2000 Daltons) may also beused as mass-tags.

The terms “measurable affinity” and “measurably inhibit,” as usedherein, means a measurable change in an IRAK protein kinase activitybetween a sample comprising a compound of the present invention, orcomposition thereof, and an IRAK protein kinase, and an equivalentsample comprising an IRAK protein kinase, in the absence of saidcompound, or composition thereof.

3. Description of Exemplary Embodiments

As described above, in certain embodiments, the present inventionprovides a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:IRAK is an IRAK binding moiety capable of binding to one or more ofIRAK-1, -2, -3, or -4;L is a bivalent moiety that connects IRAK to DIM; andDIM is a degradation inducing moiety.

In some embodiments, the present invention provides a compound offormula I:

or a pharmaceutically acceptable salt thereof, wherein:IRAK is an IRAK4 binding moiety;L is a bivalent moiety that connects IRAK to DIM; andDIM is an E3 ubiquitin ligase binding moiety, a lysine mimetic, or ahydrogen atom.

IRAK Binding Moiety (IRAK)

In certain embodiments, the present invention provides a compound offormula I, where IRAK is an IRAK4 binding moiety thereby forming acompound of formula I-a:

or a pharmaceutically acceptable salt thereof, wherein DIM and L are asdefined and described herein, and

wherein:

-   each R^(x) is independently hydrogen, deuterium, R^(z), halogen,    —CN, —NO₂, —OR, SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —CFR₂, —CF₂R,    —CF₃, —CR₂(OR), —CR₂(NR₂), —C(O)R, —C(O)OR, —C(O)NR₂, —C(S)NR₂,    —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)NR₂, —N(R)S(O)₂R, —N⁺(O)R₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)NR₂, —OP(O)(NR₂)₂, —P(O)R₂, —SiR₃, —Si(OR)R₂, or

or

-   -   two R^(x) groups are optionally taken together to form an        optionally substituted 5-7 membered partially unsaturated or        aryl fused ring having 0-3 heteroatoms independently selected        from nitrogen, oxygen, or sulfur;

-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 3-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same carbon or nitrogen are optionally taken        together with their intervening atoms to form a 4-7 membered        saturated, partially unsaturated, or heteroaryl ring having 0-3        heteroatoms, in addition to the carbon or nitrogen,        independently selected from nitrogen, oxygen, and sulfur;

-   each R^(y) is independently hydrogen, deuterium, R^(z), halogen,    —CN, —NO₂, —OR, SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —CF₂R, —CF₃,    —CR₂(OR), —CR₂(NR₂), —C(O)R, —C(O)OR, —C(O)NR₂, —C(S)NR₂,    —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)NR₂, —N(R)S(O)₂R, —OP(O)R₂, —OP(O)(OR)₂, —OP(O)(OR)NR₂,    —OP(O)(NR₂)₂, —SiR₃, —SF₅, or

-   each R^(z) is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring Q is selected from benzo or a fused 5-6 membered heteroaryl    ring having 1-3 heteroatoms independently selected from nitrogen,    oxygen, and sulfur;-   Ring T is selected from phenyl, a 4-11 membered saturated or    partially unsaturated monocyclic, bicyclic, bridged bicyclic, or    spirocyclic carbocyclic or heterocyclic ring having 1-3 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, or a 5-10    membered monocyclic or bicyclic heteroaryl ring having 1-4    heteroatoms independently selected from nitrogen, oxygen, and    sulfur, wherein Ring T is further optionally substituted with 1-2    oxo groups;-   L^(x) is a covalent bond or a C₁₋₃ bivalent straight or branched    saturated or unsaturated hydrocarbon chain wherein 1-2 methylene    units of the chain are independently and optionally replaced with    -Cy^(x)-, —O—, —S—, —C(O)—, —C(S)—, —CR₂—, —CRF—, —CF₂—, —NR—,    —N═CR—, —CR═CR—, or —S(O)₂—, wherein R of —CR₂—, —CRF—, —NR—,    —N═CR—, or —CR═CR— can combine with R^(x) or R^(y) to form a 4-7    membered saturated or partially unsaturated carbocyclic or    heterocyclic ring having 1-3 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   -Cy^(x)- is an optionally substituted ring selected from a 3-5    membered saturated or partially unsaturated carbocyclic or    heterocyclic ring having 0-3 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, or a 5 membered heteroaryl ring having    1-4 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, wherein -Cy^(x)- is optionally substituted with 1-2 oxo    groups;-   X is a covalent bond or an optionally substituted bivalent ring    selected from phenylenyl, a 4-11 membered saturated or partially    unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic    carbocyclylenyl or heterocyclylenyl having 1-3 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, or a 5-6    membered heteroarylenyl having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur;-   each x is 0, 1, 2, 3 or 4; and-   each y is 0, 1, 2, 3 or 4.

As defined generally above, each R^(x) is independently hydrogen,deuterium, R^(z), halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R,—S(O)₂NR₂, —S(O)R, —CFR₂, —CF₂R, —CF₃, —CR₂(OR), —CR₂(NR₂), —C(O)R,—C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,—N(R)C(O)R, —N(R)C(O)NR₂, —N(R)S(O)₂R, —N⁺(O⁻)R₂, —OP(O)R₂, —OP(O)(OR)₂,—OP(O)(OR)NR₂, —OP(O)(NR₂)₂, —P(O)R₂, —SiR₃, —Si(OR)R₂, or

or two R^(x) groups are optionally taken together to form an optionallysubstituted 5-7 membered partially unsaturated or aryl fused ring having0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, each R^(x) is independently hydrogen. In someembodiments, R^(x) is deuterium. In some embodiments, each R^(x) isindependently R^(z). In some embodiments, each R^(x) is independentlyhalogen. In some embodiments, each R^(x) is independently —CN. In someembodiments, each R^(x) is independently —NO₂. In some embodiments, eachR^(x) is independently —OR. In some embodiments, each R^(x) isindependently —SR. In some embodiments, each R^(x) is independently—NR₂. In some embodiments, each R^(x) is independently —S(O)₂R. In someembodiments, each R^(x) is independently —S(O)₂NR₂. In some embodiments,each R^(x) is independently —S(O)R. In some embodiments, each R^(x) isindependently —CFR₂. In some embodiments, each R^(x) is independently—CF₂R. In some embodiments, each R^(x) is independently —CF₃. In someembodiments, each R^(x) is independently —CR₂(OR). In some embodiments,each R^(x) is independently —CR₂(NR₂). In some embodiments, each R^(x)is independently —C(O)R. In some embodiments, each R^(x) isindependently —C(O)OR. In some embodiments, each R^(x) is independently—C(O)NR₂. In some embodiments, each R^(x) is independently —N⁺(O⁻)R₂. Insome embodiments, each R^(x) is independently —OP(O)R₂. In someembodiments, each R^(x) is independently —OP(O)(OR)₂. In someembodiments, each R^(x) is independently —OP(O)(OR)NR₂. In someembodiments, each R^(x) is independently —OP(O)(NR₂)₂. In someembodiments each R^(x) is independently —P(O)R₂. In some embodiments,each R^(x) is independently —SiR₃. In some embodiments, each R^(x) isindependently —Si(OR)R₂. In some embodiments, each R^(x) isindependently —SF₅. In some embodiments, each R^(x) is independently

In some embodiments, two R^(x) groups are optionally taken together toform an optionally substituted 5-7 membered partially unsaturated oraryl fused ring having 0-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

In some embodiments, R^(x) is fluoro. In some embodiments, R^(x) is

In some embodiments, R^(x) is —CF₂H. In some embodiments, R^(x) is —OMe.In some embodiments, R^(x) is -Me. In some embodiments, R^(x) is —OCF₂H.In some embodiments, R^(x) is —OCF₃. In some embodiments, R^(x) is

In some embodiments, R^(x) is

In some embodiments, R^(x) is

In some embodiments, R^(x) is

In some embodiments, each R^(x) is selected from those depicted in Table1, below.

As generally defined above, each R is independently hydrogen, or anoptionally substituted group selected from C₁₋₆ aliphatic, phenyl, a 4-7membered saturated or partially unsaturated heterocyclic having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur,and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, or two R groups on the samecarbon or nitrogen are optionally taken together with their interveningatoms to form a 4-7 membered saturated, partially unsaturated, orheteroaryl ring having 0-3 heteroatoms, in addition to the carbon ornitrogen, independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, each R is independently hydrogen. In someembodiments, each R is an optionally substituted group selected fromC₁₋₆ aliphatic. In some embodiments, each R is an optionally substitutedphenyl. In some embodiments, each R is an optionally substituted 4-7membered saturated or partially unsaturated heterocyclic having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, each R is an optionally substituted 5-6 memberedheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, two R groups on thesame nitrogen are optionally taken together with their intervening atomsto form an optionally substituted 4-7 membered saturated, partiallyunsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition tothe nitrogen, independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, each R is selected from those depicted in Table 1,below.

As defined generally above, each R^(y) is independently hydrogen,deuterium, R^(z), halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R,—S(O)₂NR₂, —S(O)R, —CFR₂, —CF₂R, —CF₃, —CR₂(OR), —CR₂(NR₂), —C(O)R,—C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,—N(R)C(O)R, —N(R)C(O)NR₂, —N(R)S(O)₂R, —N⁺(O)R₂, —OP(O)R₂, —OP(O)(OR)₂,—OP(O)(OR)NR₂, —OP(O)(NR₂)₂, —P(O)R₂, —SiR₃, —Si(OR)R₂, —SF₅, or

or two R^(y) groups are optionally taken together to form an optionallysubstituted 5-6 membered partially unsaturated or aryl fused ring having0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, each R^(y) is independently hydrogen. In someembodiments, R^(y) is deuterium. In some embodiments, each R^(y) isindependently R^(z). In some embodiments, each R^(y) is independentlyhalogen. In some embodiments, each R^(y) is independently —CN. In someembodiments, each R^(y) is independently —NO₂. In some embodiments, eachR^(y) is independently —OR. In some embodiments, each R^(y) isindependently —SR. In some embodiments, each R^(y) is independently—NR₂. In some embodiments, each R^(y) is independently —S(O)₂R. In someembodiments, each R^(y) is independently —S(O)₂NR₂. In some embodiments,each R^(y) is independently —S(O)R. In some embodiments, each R^(y) isindependently —CFR₂. In some embodiments, each R^(y) is independently—CF₂R. In some embodiments, each R^(x) is independently —CF₃. In someembodiments, each R^(y) is independently —CR₂(OR). In some embodiments,each R^(y) is independently —CR₂(NR₂). In some embodiments, each R^(y)is independently —C(O)R. In some embodiments, each R^(y) isindependently —C(O)OR. In some embodiments, each R^(y) is independently—C(O)NR₂. In some embodiments, each R^(y) is independently —N⁺(O⁻)R₂. Insome embodiments, each R^(y) is independently —OP(O)R₂. In someembodiments, each R^(y) is independently —OP(O)(OR)₂. In someembodiments, each R^(y) is independently —OP(O)(OR)NR₂. In someembodiments, each R^(y) is independently —OP(O)(NR₂)₂. In someembodiments each R^(y) is independently —P(O)R₂. In some embodiments,each R^(y) is independently —SiR₃. In some embodiments, each R^(y) isindependently —Si(OR)R₂. In some embodiments, each R^(y) isindependently —SF₅. In some embodiments, each R^(y) is independently

In some embodiments, two R^(y) groups are optionally taken together toform an optionally substituted 5-6 membered partially unsaturated oraryl fused ring having 0-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

In some embodiments, R^(y) is —CF₂Me. In some embodiments, R^(y) is—CFMe₂. In some embodiments, R^(y) is -Me. In some embodiments, R^(y) is—OCF₃. In some embodiments, R^(y) is fluoro.

In some embodiments, each R^(y) is selected from those depicted in Table1, below.

As generally defined above, each R^(z) is independently an optionallysubstituted group selected from C₁₋₆ aliphatic, phenyl, a 4-7 memberedsaturated or partially unsaturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur,and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur.

In some embodiments, each R^(z) is independently an optionallysubstituted group selected from C₁₋₆ aliphatic. In some embodiments,each R^(z) is independently an optionally substituted phenyl. In someembodiments, each R^(z) is independently an optionally substituted 4-7membered saturated or partially unsaturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, each R^(z) is independently an optionally substituted5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur.

In some embodiments, each R^(z) is selected from those depicted in Table1, below.

As generally defined above, Ring Q is selected from benzo or a fused 5-6membered heteroaryl ring having 1-3 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur.

In some embodiments, Ring Q is benzo. In some embodiments, Ring Q is afused 5-6 membered heteroaryl ring having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur.

In some embodiments, Ring Q is

In some embodiments, Ring Q is

In some embodiments, Ring Q is

In some embodiments, each Ring Q is selected from those depicted inTable 1, below.

As generally defined above, Ring T is selected from phenyl, a 4-11membered saturated or partially unsaturated monocyclic, bicyclic,bridged bicyclic, or spirocyclic carbocyclic or heterocyclic ring having1-3 heteroatoms independently selected from nitrogen, oxygen, andsulfur, or a 5-10 membered monocyclic or bicyclic heteroaryl ring having1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur, wherein Ring T is further optionally substituted with 1-2 oxogroups.

In some embodiments, Ring T is from phenyl. In some embodiments, Ring Tis a 4-11 membered saturated or partially unsaturated monocyclic,bicyclic, bridged bicyclic, or spirocyclic carbocyclic or heterocyclicring having 1-3 heteroatoms independently selected from nitrogen,oxygen, and sulfur. In some embodiments, Ring T is a 5-10 memberedmonocyclic or bicyclic heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, Ring T is further optionally substituted with 1-2 oxogroups.

In some embodiments, Ring T is

In some embodiments, Ring T is

In some embodiments, Ring T is

In some embodiments, Ring T is

In some embodiments, Ring T is

In some embodiments, Ring T is phenyl. In some embodiments, Ring T is

In some embodiments, Ring T is

In some embodiments, Ring T is

In some embodiments, Ring T is selected from those depicted in Table 1,below.

As generally defined above, L^(x) is a covalent bond or a C₁₋₃ bivalentstraight or branched saturated or unsaturated hydrocarbon chain wherein1-2 methylene units of the chain are independently and optionallyreplaced with -Cy^(x)-, —O—, —S—, —C(O)—, —C(S)—, —CR₂—, —CRF—, —CF₂—,—NR—, —N═CR—, —CR═CR—, or —S(O)₂—, wherein R of —CR₂—, —CRF—, —NR—,—N═CR—, or —CR═CR— can combine with R^(x) or R^(y) to form a 4-7membered saturated or partially unsaturated carbocyclic or heterocyclicring having 1-3 heteroatoms independently selected from nitrogen,oxygen, and sulfur.

In some embodiments, L^(x) is a covalent bond. In some embodiments,L^(x) is a C₁₋₃ bivalent straight or branched saturated or unsaturatedhydrocarbon chain wherein 1-2 methylene units of the chain areindependently and optionally replaced with -Cy^(x)-, —O—, —S—, —C(O)—,—C(S)—, —CR₂—, —CRF—, —CF₂—, —NR—, —N═CR—, —CR═CR—, or —S(O)₂—. In someembodiments, R of —CR₂—, —CRF—, —NR—, —N═CR—, or —CR═CR— can combinewith R^(x) or R^(y) to form a 4-7 membered saturated or partiallyunsaturated carbocyclic or heterocyclic ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur.

In some embodiments, Ring L^(x) is —C(O)N(H)—. In some embodiments, RingL^(x) is —CH₂C(O)N(H)—.

In some embodiments, Ring L^(x) is selected from those depicted in Table1, below.

As generally defined above, -Cy^(x)- is an optionally substituted ringselected from a 3-5 membered saturated or partially unsaturatedcarbocyclic or heterocyclic ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, or a 5 membered heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur, wherein -Cy^(x)- is optionally substituted with 1-2oxo groups.

In some embodiments, -Cy^(x)- is an optionally substituted ring selectedfrom a 3-5 membered saturated or partially unsaturated carbocyclic orheterocyclic ring having 0-3 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, -Cy^(x)- is a 5membered heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur. In some embodiments, -Cy^(x)- isoptionally substituted with 1-2 oxo groups.

In some embodiments, Ring -Cy^(x)- is selected from those depicted inTable 1, below.

As described above, X is a covalent bond or an optionally substitutedbivalent ring selected from phenylenyl, a 4-11 membered saturated orpartially unsaturated monocyclic, bicyclic, bridged bicyclic, orspirocyclic carbocyclylenyl or heterocyclylenyl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, or a 5-6membered heteroarylenyl having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur.

In some embodiments, X is a covalent bond. In some embodiments, X is4-11 membered saturated or partially unsaturated monocyclic, bicyclic,bridged bicyclic, or spirocyclic carbocyclylenyl or heterocyclylenylhaving 1-3 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In some embodiments, X is a 5-6 membered heteroarylenyl having1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur.

In some embodiments, X is

In some embodiments, X is

In some embodiments, X is

In some embodiments, X is selected from those depicted in Table 1,below.

As generally defined above, each x and y are independently 0, 1, 2, 3 or4.

In some embodiments, each x and y are independently 0. In someembodiments, each x and y are independently 1. In some embodiments, eachx and y are independently 2. In some embodiments, each x and y areindependently 3. In some embodiments, each x and y are independently 4.

In some embodiments, each x and y are selected from those depicted inTable 1, below.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and Ring T is pyridinyl as shown,to provide a compound of formula I-a-1:

or a pharmaceutically acceptable salt thereof, wherein each of DIM, L,X, R^(x), R^(y), x, and y is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and L^(x) is an amide as shown, toprovide a compound of formula I-a-2:

or a pharmaceutically acceptable salt thereof, wherein each of DIM, L,X, R^(x), R^(y), Ring T, x, and y is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and X is cyclohexyl as shown, toprovide a compound of formula I-a-3:

or a pharmaceutically acceptable salt thereof, wherein each of DIM, L,R^(x), R^(y), Ring T, x, and y is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo, X is cyclohexyl, and Ring T ispyridinyl as shown, to provide a compound of formula I-a-4:

or a pharmaceutically acceptable salt thereof, wherein each of DIM, L,R^(x), R^(y), x, and y is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo, X is cyclohexyl, and L^(x) is anamide as shown, to provide a compound of formula I-a-5:

or a pharmaceutically acceptable salt thereof, wherein each of DIM, L,R^(x), R^(y), Ring T, x, and y is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is selected from those depicted in Table 1,below.

Ligase Binding Moiety (LBM)

In certain embodiments, DIM is an E3 ubiquitin ligase binding moiety(LBM). In some embodiments, LBM is an E3 ligase ligand well known to oneof ordinary skill in the art including those described in M. Toure, C.M. Crews, Angew. Chem. Int. Ed. 2016, 55, 1966, T. Uehara et al. NatureChemical Biology 2017, 13, 675, WO 2017/176708, US 2017/0281784, WO2017/161119, WO 2017/176957, WO 2017/176958, WO 2015/160845, US2015/0291562, WO 2016/197032, WO 2016/105518, US 2018/0009779, WO2017/007612, 2018/0134684, WO 2013/106643, US 2014/0356322, WO2002/020740, US 2002/0068063, WO 2012/078559, US 2014/0302523, WO2012/003281, US 2013/0190340, US 2016/0022642, WO 2014/063061, US2015/0274738, WO 2016/118666, US 2016/0214972, WO 2016/149668, US2016/0272639, WO 2016/169989, US 2018/0118733, WO 2016/197114, US2018/0147202, WO 2017/011371, US 2017/0008904, WO 2017/011590, US2017/0037004, WO 2017/079267, US 2017/0121321, WO 2017/117473, WO2017/117474, WO 2013/106646, WO 2014/108452, WO 2017/197036, US2019/0076540, WO 2017/197046, US 2019/0076542, WO 2017/197051, US2019/0076539, WO 2017/197055, US 2019/0076541, and WO 2017/197056, theentirety of each of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a cereblon E3 ubiquitin ligase binding moietythereby forming a compound of formula I-aa:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described herein, and wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   X² is a carbon atom or silicon atom;-   X³ is a bivalent moiety selected from —CR₂—, —NR—, —O—, —S—, or    —Si(R₂)—;-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R,    —Si(OH)(R)₂, —Si(R)₃— or an optionally substituted C₁₋₄ aliphatic;-   each R² is independently hydrogen, deuterium, —R⁶, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   Ring A is a bi- or tricyclic ring selected from

wherein

-   Ring B is a fused ring selected from 6-membered aryl, 6-membered    heteroaryl containing 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur, 5 to 7-membered saturated or partially    unsaturated carbocyclyl, 5 to 7-membered saturated or partially    unsaturated heterocyclyl with 1-3 heteroatoms independently selected    from boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered    heteroaryl with 1-4 heteroatoms independently selected from    nitrogen, oxygen or sulfur;-   R³ is selected from hydrogen, halogen, —OR, —N(R)₂, or —SR;-   each R⁴ is independently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR, SR,    —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, C(O)NR₂,    —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)NR₂, or —N(R)S(O)₂R;-   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;-   each R⁶ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   L¹ is a covalent bond or a C₁₋₃ bivalent straight or branched    saturated or unsaturated hydrocarbon chain wherein 1-2 methylene    units of the chain are independently and optionally replaced with    —O—, —C(O)—, —C(S)—, —C(R)₂—, —CH(R)—, —C(F)₂—, —N(R)—, —S—, —S(O)₂—    or —(C)═CH—;-   m is 0, 1, 2, 3 or 4;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are optionally taken together        with their intervening atoms to form a 4-7 membered saturated,        partially unsaturated, or heteroaryl ring having 0-3        heteroatoms, in addition to the nitrogen, independently selected        from nitrogen, oxygen, and sulfur.

Where a point of attachment of —(R²)_(m) is depicted on Ring B, it isintended, and one of ordinary skill in the art would appreciate, thatthe point of attachment of —(R²)_(m) may be on Ring A and may also be atany available carbon or nitrogen atom on Ring A including the ring towhich Ring B is fused. Where —R² is attached to a nitrogen atom bound toR⁴ or R⁵, R⁴ or R⁵ is absent and —R² takes the place of the R⁴ or R⁵group. Where —R² is attached to a carbon atom bound to R³, R³ is absentand —R² takes the place of the R³ group.

In some embodiments, a compound of formula I-aa above is provided as acompound of formula I-aa′ or formula I-aa″:

or a pharmaceutically acceptable salt thereof, wherein:

-   each of IRAK, Ring A, L, L¹, R¹, R², X¹, X², X³, and m is as defined    above.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-bb:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   X² is a carbon atom or silicon atom;-   X³ is a bivalent moiety selected from —CR₂—, —NR—, —O—, —S—, or    —Si(R₂)—;-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R,    —Si(OH)(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R² is independently hydrogen, deuterium, —R⁶, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   Ring A is a bi- or tricyclic ring selected from

wherein Ring B is other than imidazo or benzo,

wherein Ring B is other than benzo,

wherein Ring B is other than benzo,

wherein Ring B is other than benzo,

wherein

-   Ring B is a fused ring selected from 6-membered aryl, 6-membered    heteroaryl containing 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur, 5 to 7-membered saturated or partially    unsaturated carbocyclyl, 5 to 7-membered saturated or partially    unsaturated heterocyclyl with 1-3 heteroatoms independently selected    from boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered    heteroaryl with 1-4 heteroatoms independently selected from    nitrogen, oxygen or sulfur;-   R³ is selected from hydrogen, halogen, —OR, —N(R)₂, or —SR;-   each R⁴ is independently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR, SR,    —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, C(O)NR₂,    —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)NR₂, or —N(R)S(O)₂R;-   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;-   each R⁶ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   m is 0, 1, 2, 3 or 4; and-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are optionally taken together        with their intervening atoms to form a 4-7 membered saturated,        partially unsaturated, or heteroaryl ring having 0-3        heteroatoms, in addition to the nitrogen, independently selected        from nitrogen, oxygen, and sulfur.

Where a point of attachment of —(R²)_(m) is depicted on Ring B, it isintended, and one of ordinary skill in the art would appreciate, thatthe point of attachment of —(R²)_(m) may be on Ring A and may also be atany available carbon or nitrogen atom on Ring A including the ring towhich Ring B is fused. Where —R² is attached to a nitrogen atom bound toR⁴ or R⁵, R⁴ or R⁵ is absent and —R² takes the place of the R⁴ or R⁵group. Where —R² is attached to a carbon atom bound to R³, R³ is absentand —R² takes the place of the R³ group.

In some embodiments, the compound of formula I-bb above is provided as acompound of formula I-bb′ or formula I-bb″:

or a pharmaceutically acceptable salt thereof, wherein:

-   each of IRAK, Ring A, L, R¹, R², X¹, X², X³, and m is as defined    above.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-cc:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —C(O)—, —C(S)—, or

-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —NR₂, or an optionally substituted C₁₋₄ aliphatic;-   each R² is independently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR, SR,    —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, C(O)NR₂,    —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)NR₂, or —N(R)S(O)₂R;-   Ring A is a bi- or tricyclic ring selected from

wherein

-   Ring B is a fused ring selected from 6-membered aryl, 6-membered    heteroaryl containing 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, 5 to 7-membered saturated or partially    unsaturated carbocyclyl, 5 to 7-membered saturated or partially    unsaturated heterocyclyl with 1-3 heteroatoms independently selected    from boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered    heteroaryl with 1-4 heteroatoms independently selected from    nitrogen, oxygen or sulfur;-   R³ is selected from hydrogen, halogen, —OR, —N(R)₂, or —SR;-   each R⁴ is independently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR, SR,    —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, C(O)NR₂,    —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)NR₂, or —N(R)S(O)₂R;-   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;-   each R⁶ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   m is 0, 1, 2, 3 or 4; and-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are optionally taken together        with their intervening atoms to form a 4-7 membered saturated,        partially unsaturated, or heteroaryl ring having 0-3        heteroatoms, in addition to the nitrogen, independently selected        from nitrogen, oxygen, and sulfur.

Where a point of attachment of —(R²)_(m) is depicted on Ring B, it isintended, and one of ordinary skill in the art would appreciate, thatthe point of attachment of —(R²)_(m) may be on Ring A and may also be atany available carbon or nitrogen atom on Ring A including the ring towhich Ring B is fused. Where —R² is attached to a nitrogen atom bound toR⁴ or R⁵, R⁴ or R⁵ is absent and —R² takes the place of the R⁴ or R⁵group. Where —R² is attached to a carbon atom bound to R³, R³ is absentand —R² takes the place of the R³ group.

In some embodiments, the compound of formula I-cc above is provided as acompound of formula I-cc′ or formula I-cc″:

or a pharmaceutically acceptable salt thereof, wherein:

-   each of IRAK, Ring A, L, R¹, R², X¹, and m is as defined above.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-dd:

or a pharmaceutically acceptable salt thereof, wherein, L and IRAK areas defined above and described in embodiments herein, and wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   X² is a carbon atom or silicon atom;-   X³ is a bivalent moiety selected from —CR₂—, —NR—, —O—, —S—, or    —Si(R₂)—;-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —NR₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R, —Si(OH)(R)₂,    —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   Ring C is a mono- or bicyclic ring selected from

-   each of R² and R^(3a) is independently hydrogen, deuterium, —R⁶,    halogen, —CN, —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂,    —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   Ring D is selected from a 6-membered aryl, 6-membered heteroaryl    containing 1-4 heteroatoms independently selected from nitrogen,    oxygen, and sulfur, 5 to 7-membered saturated or partially    unsaturated carbocyclyl, 5 to 7-membered saturated or partially    unsaturated heterocyclyl with 1-3 heteroatoms independently selected    from boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered    heteroaryl with 1-4 heteroatoms independently selected from    nitrogen, oxygen or sulfur;-   each R⁴ is independently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR, SR,    —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, C(O)NR₂,    —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)NR₂, or —N(R)S(O)₂R;-   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;-   each R⁶ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   L¹ is a covalent bond or a C₁₋₃ bivalent straight or branched    saturated or unsaturated hydrocarbon chain wherein 1-2 methylene    units of the chain are independently and optionally replaced with    —O—, —C(O)—, —C(S)—, —C(R)₂—, —CH(R)—, —C(F)₂—, —N(R)—, —S—, —S(O)₂—    or —(C)═CH—;-   m is 0, 1, 2, 3 or 4;-   n is 0, 1, 2, 3 or 4;-   p is 0 or 1, wherein when p is 0, the bond connecting Ring C and    Ring D is connected to

and

-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are optionally taken together        with their intervening atoms to form a 4-7 membered saturated,        partially unsaturated, or heteroaryl ring having 0-3        heteroatoms, in addition to the nitrogen, independently selected        from nitrogen, oxygen, and sulfur.

In some embodiments, a compound of formula I-dd above is provided as acompound of formula I-dd′ or formula I-dd″:

or a pharmaceutically acceptable salt thereof, wherein:

-   each of IRAK, Ring C, Ring D, L, L¹, R¹, R², R^(3a), X¹, X², X³, n,    m, and p is as defined above.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-ee:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —C(O)—, —C(S)—, or

-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —NR₂, or an optionally substituted C₁₋₄ aliphatic;-   Ring C is a mono- or bicyclic ring selected from

-   each of R² and R^(3a) is independently hydrogen, —R⁶, halogen, —CN,    —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR,    C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)NR₂, or —N(R)S(O)₂R;-   Ring D is selected from 6-membered aryl, 6-membered heteroaryl    containing 1-4 heteroatoms independently selected from nitrogen,    oxygen, and sulfur, 5 to 7-membered saturated or partially    unsaturated carbocyclyl, 5 to 7-membered saturated or partially    unsaturated heterocyclyl with 1-3 heteroatoms independently selected    from boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered    heteroaryl with 1-4 heteroatoms independently selected from    nitrogen, oxygen or sulfur;-   each R⁴ is independently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR, SR,    —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, C(O)NR₂,    —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)NR₂, or —N(R)S(O)₂R;-   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;-   each R⁶ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   m is 0, 1, or 2;-   n is 0, 1, 2, 3 or 4;-   p is 0 or 1, wherein when p is 0, the bond connecting Ring C and    Ring D is connected to

-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are optionally taken together        with their intervening atoms to form a 4-7 membered saturated,        partially unsaturated, or heteroaryl ring having 0-3        heteroatoms, in addition to the nitrogen, independently selected        from nitrogen, oxygen, and sulfur.

In some embodiments, a compound of formula I-ee above is provided as acompound of formula I-ee′ or formula I-ee″:

or a pharmaceutically acceptable salt thereof, wherein:

-   each of IRAK, Ring C, Ring D, L, R¹, R², R^(3a), X¹, n, m, and p is    as defined above.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-ff:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   X² is a carbon atom or silicon atom;-   X³ is a bivalent moiety selected from —CR₂—, —NR—, —O—, —S—, or    —Si(R₂)—;-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —NR₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R, —Si(OH)(R)₂,    —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   Ring C is a mono- or bicyclic ring selected from

-   each or R² and R^(3a) is independently hydrogen, deuterium, —R⁶,    halogen, —CN, —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂,    —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   Ring D is selected from 6-membered aryl, 6-membered heteroaryl    containing 1-4 heteroatoms independently selected from nitrogen,    oxygen, and sulfur, 5 to 7-membered saturated or partially    unsaturated carbocyclyl, 5 to 7-membered saturated or partially    unsaturated heterocyclyl with 1-3 heteroatoms independently selected    from boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered    heteroaryl with 1-4 heteroatoms independently selected from    nitrogen, oxygen or sulfur;-   each R⁴ is independently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR, SR,    —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, C(O)NR₂,    —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)NR₂, or —N(R)S(O)₂R;-   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;-   each R⁶ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   L¹ is a covalent bond or a C₁₋₃ bivalent straight or branched    saturated or unsaturated hydrocarbon chain wherein 1-2 methylene    units of the chain are independently and optionally replaced with    —O—, —C(O)—, —C(S)—, —C(R)₂—, —CH(R)—, —C(F)₂—, —N(R)—, —S—, —S(O)₂—    or —(C)═CH—;-   m is 0, 1, 2, 3 or 4;-   n is 0, 1, 2, 3 or 4;-   p is 0 or 1; and-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are optionally taken together        with their intervening atoms to form a 4-7 membered saturated,        partially unsaturated, or heteroaryl ring having 0-3        heteroatoms, in addition to the nitrogen, independently selected        from nitrogen, oxygen, and sulfur.

In some embodiments, a compound of formula I-ff above is provided as acompound of formula I-ff′ or formula I-ff″:

or a pharmaceutically acceptable salt thereof, wherein:

-   each of IRAK, Ring C, Ring D, L, L¹, R¹, R², R^(3a), X¹, X², X³, m,    n, and p is as defined above.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-gg:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —C(O)—, —C(S)—, or

-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —NR₂, or an optionally substituted C₁₋₄ aliphatic;-   Ring C is a mono- or bicyclic ring selected from

-   each of R², R^(3a), and R⁴ is independently hydrogen, —R⁶, halogen,    —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R,    —C(O)OR, C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,    —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;-   Ring D is selected from 6-membered aryl, 6-membered heteroaryl    containing 1-4 heteroatoms independently selected from nitrogen,    oxygen, and sulfur, 5 to 7-membered saturated or partially    unsaturated carbocyclyl, 5 to 7-membered saturated or partially    unsaturated heterocyclyl with 1-3 heteroatoms independently selected    from boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered    heteroaryl with 1-4 heteroatoms independently selected from    nitrogen, oxygen or sulfur;-   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;-   each R⁶ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   m is 0, 1, or 2;-   n is 0, 1, 2, 3, or 4;-   p is 0 or 1; and-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are optionally taken together        with their intervening atoms to form a 4-7 membered saturated,        partially unsaturated, or heteroaryl ring having 0-3        heteroatoms, in addition to the nitrogen, independently selected        from nitrogen, oxygen, and sulfur.

In some embodiments, a compound of formula I-gg above is provided as acompound of formula I-gg′ or formula I-gg″:

or a pharmaceutically acceptable salt thereof, wherein:

-   each of IRAK, Ring C, Ring D, L, R¹, R², R^(3a), X¹, m, n, and p is    as defined above.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-hh:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   X² is a carbon atom, nitrogen atom, or silicon atom;-   X³ is a bivalent moiety selected from a covalent bond, —CR₂—, —NR—,    —O—, —S—, or —SiR₂—;-   R¹ is absent, hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R,    —S(O)₂R, —NR₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R,    —Si(OH)R₂, —SiR₃— or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R⁶, halogen, —CN,    —NO₂, —OR, —SR, —NR₂, —SiR₃, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R,    —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)NR₂, —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,    —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂, —N(R)P(O)(OR)NR₂,    —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each R⁶ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   each of Ring E, Ring F, and Ring G is independently a fused ring    selected from 6-membered aryl, 6-membered heteroaryl containing 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl with 1-3    heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms    independently selected from nitrogen, oxygen or sulfur;-   L¹ is a covalent bond or a C₁₋₃ bivalent straight or branched    saturated or unsaturated hydrocarbon chain wherein 1-2 methylene    units of the chain are independently and optionally replaced with    —O—, —C(O)—, —C(S)—, —C(R)₂—, —CH(R)—, —C(F)₂—, —N(R)—, —S—, —S(O)₂—    or —(C)═CH—; and-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

Where a point of attachment of

is depicted on Ring E, Ring F, or Ring G, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on any available carbon or nitrogen atom on Ring E, Ring F, orRing G, including the ring to which Ring E or Ring G is fused to Ring F.

Where a point of attachment of —(R²)_(m) is depicted on Ring E, Ring F,or Ring G, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be at anyavailable carbon or nitrogen atom on Ring E, Ring F, or Ring G includingthe carbon atom to which Ring E or Ring G is fused to Ring F.

Where a point of attachment of

is depicted on Ring E, Ring F, or Ring G, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on any available carbon or nitrogen atom on Ring E, Ring F, orRing G, including the carbon atom to which Ring E or Ring G is fused toRing F.

In some embodiments, a compound of formula I-hh above is provided as acompound of formula I-hh′ or formula I-hh″:

or a pharmaceutically acceptable salt thereof, wherein:

-   each of IRAK, Ring E, Ring F, Ring G, L, L¹, R¹, R², X¹, X², X³, and    m is as defined above.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-hh-1 or I-hh-2:

or a pharmaceutically acceptable salt thereof, wherein F and IRAK are asdefined above and described in embodiments herein, and wherein:

-   each R² is independently hydrogen, deuterium, —R⁶, halogen, —CN,    —NO₂, —OR, —SR, —NR₂, —SiR₃, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R,    —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)NR₂, —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,    —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂, —N(R)P(O)(OR)NR₂,    —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each R⁶ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   each of Ring E, Ring F, and Ring G is independently a fused ring    selected from 6-membered aryl, 6-membered heteroaryl containing 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl with 1-3    heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms    independently selected from nitrogen, oxygen or sulfur;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   L¹ is a covalent bond or a C₁₋₃ bivalent straight or branched    saturated or unsaturated hydrocarbon chain wherein 1-2 methylene    units of the chain are independently and optionally replaced with    —O—, —C(O)—, —C(S)—, —C(R)₂—, —CH(R)—, —C(F)₂—, —N(R)—, —S—, —S(O)₂—    or —(C)═CH—;-   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16;    and-   R⁴, R¹⁰, R¹¹, R¹⁵, W¹, W², and X is as defined in WO 2019/099868,    the entirety of each of which is herein incorporated by reference.

Where a point of attachment of

is depicted on Ring E, Ring F, or Ring G, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on any available carbon or nitrogen atom on Ring E, Ring F, orRing G, including the ring to which Ring E or Ring G is fused to Ring F.

Where a point of attachment of —(R²)_(m) is depicted on Ring E, Ring F,or Ring G, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be at anyavailable carbon or nitrogen atom on Ring E, Ring F, or Ring G includingthe carbon atom to which Ring E or Ring G is fused to Ring F.

Where a point of attachment of

is depicted on Ring E, Ring F, or Ring G, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on any available carbon or nitrogen atom on Ring E, Ring F, orRing G, including the carbon atom to which Ring E or Ring G is fused toRing F.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-ii:

or a pharmaceutically acceptable salt thereof, wherein F and IRAK are asdefined above and described in embodiments herein, and wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —C(O)—, —C(S)—, or

-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R⁶, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, or —N(R)S(O)₂R;-   each R⁶ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   each of Ring E, Ring F, and Ring G is independently a fused ring    selected from 6-membered aryl containing 0-3 nitrogens, 5 to    7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl with 1-3    heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-3 heteroatoms    independently selected from nitrogen, oxygen or sulfur; and-   m is 0, 1, 2, 3, or 4.

Where a point of attachment of

is depicted on Ring E, Ring F, or Ring G, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on any available carbon or nitrogen atom on Ring E, Ring F, orRing G, including the ring to which Ring E or Ring G is fused to Ring F.

Where a point of attachment of —(R²)_(m) is depicted on Ring E, Ring F,or Ring G, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be at anyavailable carbon or nitrogen atom on Ring E, Ring F, or Ring G includingthe carbon atom to which Ring E or Ring G is fused to Ring F.

In some embodiments, a compound of formula I-ii above is provided as acompound of formula I-ii′ or formula I-ii″:

or a pharmaceutically acceptable salt thereof, wherein:

-   each of IRAK, L, Ring E, Ring F, Ring G, L, R¹, R², X¹, and m is as    defined above.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-jj:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   X² is a carbon atom, nitrogen atom, or silicon atom;-   X³ is a bivalent moiety selected from a covalent bond, —CR₂—, —NR—,    —O—, —S—, or —SiR₂—;-   R¹ is absent, hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R,    —S(O)₂R, —NR₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R,    —Si(OH)R₂, —SiR₃— or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R⁶, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each R⁶ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring E is a fused ring selected from 6-membered aryl, 6-membered    heteroaryl containing 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur, 5 to 7-membered saturated or partially    unsaturated carbocyclyl, 5 to 7-membered saturated or partially    unsaturated heterocyclyl with 1-3 heteroatoms independently selected    from boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered    heteroaryl with 1-4 heteroatoms independently selected from    nitrogen, oxygen or sulfur;-   Ring H is a fused ring selected from a 7-9 membered saturated or    partially unsaturated carbocyclyl or heterocyclyl ring with 1-3    heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, wherein Ring E is optionally further substituted    with 1-2 oxo groups;-   L¹ is a covalent bond or a C₁₋₃ bivalent straight or branched    saturated or unsaturated hydrocarbon chain wherein 1-2 methylene    units of the chain are independently and optionally replaced with    —O—, —C(O)—, —C(S)—, —C(R)₂—, —CH(R)—, —C(F)₂—, —N(R)—, —S—, —S(O)₂—    or —(C)═CH—;-   m is 0, 1, 2, 3, or 4.

Where a point of attachment of

is depicted on Ring E or Ring H, it is intended, and one of ordinaryskill in the art would appreciate, that the point of attachment of

may be on any available carbon or nitrogen atom on Ring E or Ring Hincluding the carbon atom to which Ring E and Ring H are fused.

Where a point of attachment of —(R²)_(m) is depicted on Ring E and RingH, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be on anyavailable carbon or nitrogen atom on Ring E or Ring H including thecarbon atom to which Ring E and Ring H are fused.

Where a point of attachment of

is depicted on Ring E and Ring H, it is intended, and one of ordinaryskill in the art would appreciate, that the point of attachment of

may be on any available carbon or nitrogen atom on Ring E or Ring Hincluding the carbon atom to which Ring E and Ring H are fused.

In some embodiments, a compound of formula I-jj above is provided as acompound of formula I-jj′ or formula I-jj″:

or a pharmaceutically acceptable salt thereof, wherein:

-   each of IRAK, Ring E, Ring H, L, L¹, R¹, R², X¹, X², X³, and m is as    defined above.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-kk:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —C(O)—, —C(S)—, or

-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R⁶, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, or —N(R)S(O)₂R;-   each R⁶ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring E is a fused ring selected from 6-membered aryl, 6-membered    heteroaryl containing 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur, 5 to 7-membered saturated or partially    unsaturated carbocyclyl, 5 to 7-membered saturated or partially    unsaturated heterocyclyl with 1-3 heteroatoms independently selected    from boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered    heteroaryl with 1-4 heteroatoms independently selected from    nitrogen, oxygen or sulfur;-   Ring H is a ring selected from a 7-9 membered saturated or partially    unsaturated carbocyclyl or heterocyclyl ring with 1-3 heteroatoms    independently selected from boron, nitrogen, oxygen, silicon, or    sulfur, wherein Ring E is optionally further substituted with 1-2    oxo groups; and-   m is 0, 1, 2, 3, or 4.

Where a point of attachment of

is depicted on Ring E or Ring H, it is intended, and one of ordinaryskill in the art would appreciate, that the point of attachment of

may be on any available carbon or nitrogen atom on Ring E or Ring Hincluding the carbon atom to which Ring E and Ring H are fused.

Where a point of attachment of —(R²)_(m) is depicted on Ring E and RingH, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be on anyavailable carbon or nitrogen atom on Ring E or Ring H including thecarbon atom to which Ring E and Ring H are fused.

Where a point of attachment of

is depicted on Ring E and Ring H, it is intended, and one of ordinaryskill in the art would appreciate, that the point of attachment of

may be on any available carbon or nitrogen atom on Ring E or Ring Hincluding the carbon atom to which Ring E and Ring H are fused.

In some embodiments, a compound of formula I-kk above is provided as acompound of formula I-kk′ or formula I-kk″:

or a pharmaceutically acceptable salt thereof, wherein:

-   each of IRAK, Ring E, Ring H, L, R¹, R², X¹, and m is as defined    above.

In some embodiments, the present invention provides the compound offormula I-kk wherein

-   Ring H is 1,3-dihydro-2H-1,4-diazepin-2-one, thereby forming a    compound of formula I-kk-1:

or a pharmaceutically acceptable salt thereof, wherein:

-   each of IRAK, L, Ring E, X¹, R¹, R², and m is as defined above.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-ll:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,    —C(S)—, or

-   X² is a carbon atom, nitrogen atom, or silicon atom;-   X³ is a bivalent moiety selected from a covalent bond, —CR₂—, —NR—,    —O—, —S—, or —SiR₂—;-   R¹ is absent, hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R,    —S(O)₂R, —NR₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R,    —Si(OH)R₂, —SiR₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R⁶, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,    —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each R⁶ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   each of Ring I and J is independently a fused ring selected from    6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, 5 to    7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl with 1-3    heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms    independently selected from nitrogen, oxygen or sulfur;-   Ring K is a fused ring selected from a 7-12 membered saturated or    partially unsaturated carbocyclyl or heterocyclyl ring with 1-3    heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, wherein Ring H is optionally further substituted    with 1-2 oxo groups;-   L¹ is a covalent bond or a C₁₋₃ bivalent straight or branched    saturated or unsaturated hydrocarbon chain wherein 1-2 methylene    units of the chain are independently and optionally replaced with    —O—, —C(O)—, —C(S)—, —C(R)₂—, —CH(R)—, —C(F)₂—, —N(R)—, —S—, —S(O)₂—    or —(C)═CH—; and-   m is 0, 1, 2, 3, or 4.

Where a point of attachment of

is depicted on Ring I, Ring J, and Ring K, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on any available carbon or nitrogen atom on Ring I, Ring J, orRing K, including the carbon atom to which Ring I, Ring J, and Ring Kare fused.

Where a point of attachment of —(R²)_(m) is depicted on Ring I, Ring J,and Ring K, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be on anyavailable carbon or nitrogen atom on Ring I, Ring J, or Ring K,including the carbon atom to which Ring I, Ring J, and Ring K are fused.

Where a point of attachment of

is depicted on Ring I, Ring J, and Ring K, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on any available carbon or nitrogen atom on Ring I, Ring J, orRing K, including the carbon atom to which Ring I, Ring J, and Ring Kare fused.

In some embodiments, a compound of formula I-ll above is provided as acompound of formula I-ll′ or formula I-ll″:

or a pharmaceutically acceptable salt thereof, wherein:

-   each of IRAK, Ring I, Ring J, Ring K, L, L¹, R¹, R², X¹, X², X³, and    m is as defined above.

In certain embodiments, the present invention provides a compound offormula I-mm:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein:

-   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,    —C(O)—, —C(S)—, or

-   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,    —N(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄ aliphatic;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R² is independently hydrogen, deuterium, —R⁶, halogen, —CN,    —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,    —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)N(R)₂, or —N(R)S(O)₂R;-   each R⁶ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   each of Ring I and J is independently a fused ring selected from    6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, 5 to    7-membered saturated or partially unsaturated carbocyclyl, 5 to    7-membered saturated or partially unsaturated heterocyclyl with 1-3    heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or 5-membered heteroaryl with 1-4 heteroatoms    independently selected from nitrogen, oxygen or sulfur;-   Ring K is a fused ring selected from a 7-12 membered saturated or    partially unsaturated carbocyclyl or heterocyclyl ring with 1-3    heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, wherein Ring H is optionally further substituted    with 1-2 oxo groups; and-   m is 0, 1, 2, 3, or 4.

Where a point of attachment of

is depicted on Ring I, Ring J, and Ring K, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on any available carbon or nitrogen atom on Ring I, Ring J, orRing K, including the carbon atom to which Ring I, Ring J, and Ring Kare fused.

Where a point of attachment of —(R²)_(m) is depicted on Ring I, Ring J,and Ring K, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be on anyavailable carbon or nitrogen atom on Ring I, Ring J, or Ring K,including the carbon atom to which Ring I, Ring J, and Ring K are fused.

Where a point of attachment of

is depicted on Ring I, Ring J, and Ring K, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on any available carbon or nitrogen atom on Ring I, Ring J, orRing K, including the carbon atom to which Ring I, Ring J, and Ring Kare fused.

In some embodiments, a compound of formula I-mm above is provided as acompound of formula I-mm′ or formula I-mm″:

or a pharmaceutically acceptable salt thereof, wherein:

-   each of IRAK, Ring I, Ring J, Ring K, L, R¹, R², X¹, and m is as    defined above.

In some embodiments, the present invention provides the compound offormula I-mm wherein

-   Ring J is pyrrole, thereby forming a compound of formula I-mm-1:

or a pharmaceutically acceptable salt thereof, wherein:

-   each of IRAK, L, Ring I, Ring K, X¹, R¹, R², and m is as defined    above.

As described above, in another aspect, the present invention provides acompound of Formula I-nn:

or a pharmaceutically acceptable salt thereof, wherein:

-   Ring M is selected from

-   each of X¹, X⁶, and X⁷ is independently a bivalent moiety selected    from a covalent bond, —CH₂—, —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—,    —P(O)OR—, —P(O)NR₂—, —C(O)—, —C(S)—, or

-   each of X³ and X⁵ is independently a bivalent moiety selected from a    covalent bond, —CR₂—, —NR—, —O—, —S—, or —SiR₂—;-   X⁴ is a trivalent moiety selected from

-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R^(3a) is independently hydrogen, deuterium, —R⁶, halogen, —CN,    —NO₂, —OR, —SR, —NR₂, —SiR₃, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R,    —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,    —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,    —OP(O)(OR)NR₂, —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,    —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂, —N(R)P(O)(OR)NR₂,    —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;-   each R⁶ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   each R⁷ is independently hydrogen, deuterium, halogen, —CN, —OR,    —SR, —S(O)R, —S(O)₂R, —NR₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂,    —Si(OH)R₂, —Si(OH)₂R, —SiR₃, or an optionally substituted C₁₋₄    aliphatic; or    -   R⁷ and X¹ or X³ are taken together with their intervening atoms        to form a 5-7 membered saturated, partially unsaturated,        carbocyclic ring or heterocyclic ring having 1-3 heteroatoms,        independently selected from boron, nitrogen, oxygen, silicon, or        sulfur;    -   two R⁷ groups on the same carbon are optionally taken together        with their intervening atoms to form a 3-6 membered spiro fused        ring or a 4-7 membered heterocyclic ring having 1-2 heteroatoms        independently selected from boron, nitrogen, oxygen, silicon, or        sulfur;    -   two R⁷ groups on adjacent carbon atoms are optionally taken        together with their intervening atoms to form a 3-7 membered        saturated, partially unsaturated, carbocyclic ring or        heterocyclic ring having 1-3 heteroatoms independently selected        from boron, nitrogen, oxygen, silicon, or sulfur, or a 7-13        membered saturated, partially unsaturated, bridged heterocyclic        ring, or a spiro heterocyclic ring having 1-3 heteroatoms,        independently selected from boron, nitrogen, oxygen, silicon, or        sulfur;-   Ring D is selected from 6 to 10-membered aryl or heteroaryl    containing 1-4 heteroatoms independently selected from nitrogen,    oxygen, and sulfur, 5 to 7-membered saturated or partially    unsaturated carbocyclyl, 5 to 7-membered saturated or partially    unsaturated heterocyclyl with 1-3 heteroatoms independently selected    from boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered    heteroaryl with 1-4 heteroatoms independently selected from    nitrogen, oxygen or sulfur;-   L¹ is a covalent bond or a C₁₋₃ bivalent straight or branched    saturated or unsaturated hydrocarbon chain wherein 1-2 methylene    units of the chain are independently and optionally replaced with    —O—, —C(O)—, —C(S)—, —C(R)₂—, —CH(R)—, —C(F)₂—, —N(R)—, —S—, —S(O)₂—    or —(C)═CH—;-   n is 0, 1, 2, 3, or 4; and-   q is 0, 1, 2, 3, or 4.

As defined above and described herein, each of X¹, X⁶, and X⁷ isindependently a bivalent moiety selected from a covalent bond, —CH₂—,—C(R)₂—, —C(O)—, —C(S)—, —CH(R)—, —CH(CF₃)—, —P(O)(OR)—, —P(O)(R)—,—P(O)(NR₂)—, —S(O)—, —S(O)₂—, or

In some embodiments, each of X¹, X⁶, and X⁷ is independently a covalentbond. In some embodiments, each of X¹, X⁶, and X⁷ is independently—CH₂—. In some embodiments, each of X¹, X⁶, and X⁷ is independently—CR₂—. In some embodiments, each of X¹, X⁶, and X⁷ is independently—C(O)—. In some embodiments, each of X¹, X⁶, and X⁷ is independently—C(S)—. In some embodiments, each of X¹, X⁶, and X⁷ is independently—CH(R)—. In some embodiments, each of X¹, X⁶, and X⁷ is independently—CH(CF₃)—. In some embodiments, each of X¹, X⁶, and X⁷ is independently—P(O)(OR)—. In some embodiments, each of X¹, X⁶, and X⁷ is independently—P(O)(R)—. In some embodiments, each of X¹, X⁶, and X⁷ is independently—P(O)NR₂—. In some embodiments, each of X¹, X⁶, and X⁷ is independently—S(O)—. In some embodiments, each of X¹, X⁶, and X⁷ is independently—S(O)₂—. In some embodiments, each of X¹, X⁶, and X⁷ is independently

In some embodiments, each of X¹, X⁶, and X⁷ is independently selectedfrom those depicted in Table 1 below.

As defined above and described herein, X² is a carbon atom, nitrogenatom, or silicon atom.

In some embodiments, X² is a carbon atom. In some embodiments, X² is anitrogen atom. In some embodiments, X² is a silicon atom.

In some embodiments, X² is selected from those depicted in Table 1below.

As defined above and described herein, X³ is a bivalent moiety selectedfrom —CH₂—, —CR₂—, —NR—, —CF₂—, —CHF—, —S—, —CH(R)—, —SiR₂—, or —O—.

In some embodiments, each of X³ and X⁵ is independently —CH₂—. In someembodiments, each of X³ and X⁵ is independently —CR₂—. In someembodiments, each of X³ and X⁵ is independently —NR—. In someembodiments, each of X³ and X⁵ is independently —CF₂—. In someembodiments, each of X³ and X⁵ is independently —CHF—. In someembodiments, each of X³ and X⁵ is independently —S—. In someembodiments, each of X³ and X⁵ is independently —CH(R)—. In someembodiments, each of X³ and X⁵ is independently —SiR₂—. In someembodiments, each of X³ and X⁵ is independently —O—.

In some embodiments, each of X³ and X⁵ is independently selected fromthose depicted in Table 1 below.

As defined above and described herein, X⁴ is a trivalent moiety selectedfrom

In some embodiments, X⁴ is

In some embodiments, X⁴ is

In some embodiments, X⁴ is

In some embodiments, X⁴ is

In some embodiments, X⁴ is

In some embodiments, X⁴ is

In some embodiments, X⁴ is

In some embodiments, X⁴ is selected from those depicted in Table 1below.

As defined above and described herein, R¹ is hydrogen, deuterium,halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R, —NR₂, —P(O)(OR)₂, —P(O)(NR₂)OR,—P(O)(NR₂)₂, —Si(OH)₂R, —Si(OH)R₂, —SiR₃, an optionally substituted C₁₋₄aliphatic, or R¹ and X¹ or X⁴ are taken together with their interveningatoms to form a 5-7 membered saturated, partially unsaturated,carbocyclic ring or heterocyclic ring having 1-3 heteroatoms,independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R¹ is hydrogen. In some embodiments, R¹ isdeuterium. In some embodiments, R¹ is halogen. In some embodiments, R¹is —CN. In some embodiments, R¹ is —OR. In some embodiments, R¹ is —SR.In some embodiments, R¹ is —S(O)R. In some embodiments, R¹ is —S(O)₂R.In some embodiments, R¹ is —NR₂. In some embodiments, R¹ is —P(O)(OR)₂.In some embodiments, R¹ is —P(O)(NR₂)OR. In some embodiments, R¹ is—P(O)(NR₂)₂. In some embodiments, R¹ is —Si(OH)₂R. In some embodiments,R¹ is —Si(OH)R₂. In some embodiments, R¹ is —SiR₃, In some embodiments,R¹ is an optionally substituted C₁₋₄ aliphatic. In some embodiments, R¹and X¹ or X⁴ are taken together with their intervening atoms to form a5-7 membered saturated, partially unsaturated, carbocyclic ring orheterocyclic ring having 1-3 heteroatoms, independently selected fromnitrogen, oxygen, or sulfur.

In some embodiments, R¹ is selected from those depicted in Table 1below.

As defined above and described herein, each R is independently hydrogen,deuterium, or an optionally substituted group selected from C₁₋₆aliphatic, phenyl, a 4-7 membered saturated or partially unsaturatedheterocyclic having 1-3 heteroatoms independently selected from boron,nitrogen, oxygen, silicon, and sulfur, and a 5-6 membered heteroarylring having 1-4 heteroatoms independently selected from boron, nitrogen,oxygen, silicon, and sulfur, or two R groups on the same nitrogen aretaken together with their intervening atoms to form a 4-7 memberedsaturated, partially unsaturated, or heteroaryl ring having 0-3heteroatoms, in addition to the nitrogen, independently selected fromboron, nitrogen, oxygen, silicon, and sulfur.

In some embodiments, R is hydrogen. In some embodiments, R is deuterium.In some embodiments, R is optionally substituted C₁₋₆ aliphatic. In someembodiments, R is optionally substituted phenyl. In some embodiments, Ris optionally substituted 4-7 membered saturated or partiallyunsaturated heterocyclic having 1-3 heteroatoms independently selectedfrom boron, nitrogen, oxygen, silicon, and sulfur. In some embodiments,R is optionally substituted 5-6 membered heteroaryl ring having 1-4heteroatoms independently selected from boron, nitrogen, oxygen,silicon, and sulfur. In some embodiments, two R groups on the samenitrogen are taken together with their intervening atoms to form a 4-7membered saturated, partially unsaturated, or heteroaryl ring having 0-3heteroatoms, in addition to the nitrogen, independently selected fromboron, nitrogen, oxygen, silicon, and sulfur.

In some embodiments, R is selected from those depicted in Table 1 below.

As defined above and described herein, each of R² and R^(3a) isindependently hydrogen, deuterium, —R⁶, halogen, —CN, —NO₂, —OR,—Si(OH)₂R, —Si(OH)R₂, —SR, —NR₂, SiR₃, —S(O)₂R, —S(O)₂NR₂, —S(O)R,—C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,—C(R)₂N(R)C(O)NR₂, —OC(O)R, —OC(O)NR₂, —OP(O)R₂, —OP(O)(OR)₂,—OP(O)(OR)NR₂, —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,—N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂, N(R)P(O)(OR)NR₂, —N(R)P(O)(NR₂)₂,or —N(R)S(O)₂R.

In some embodiments, R² and R^(3a) is independently hydrogen. In someembodiments, R² and R^(3a) is independently deuterium. In someembodiments, R² and R^(3a) is independently —R⁶. In some embodiments, R²and R^(3a) is independently halogen. In some embodiments, R² and R^(3a)is independently —CN. In some embodiments, R² and R^(3a) isindependently —NO₂. In some embodiments, R² and R^(3a) is independently—OR. In some embodiments, R² and R^(3a) is independently —Si(OH)₂R. Insome embodiments, R² and R^(3a) is independently —Si(OH)R₂. In someembodiments, R² and R^(3a) is independently —SR. In some embodiments, R²and R^(3a) is independently —NR₂. In some embodiments, R² and R^(3a) isindependently —SiR₃, In some embodiments, R² and R^(3a) is independently—S(O)₂R. In some embodiments, R² and R^(3a) is independently —S(O)₂NR₂.In some embodiments, R² and R^(3a) is independently —S(O)R. In someembodiments, R² and R^(3a) is independently —C(O)R. In some embodiments,R² and R^(3a) is independently —C(O)OR. In some embodiments, R² andR^(3a) is independently —C(O)NR₂. In some embodiments, R² and R^(3a) isindependently —C(O)N(R)OR. In some embodiments, R² and R^(3a) isindependently —C(R)₂N(R)C(O)R. In some embodiments, R² and R^(3a) isindependently —C(R)₂N(R)C(O)NR₂. In some embodiments, R² and R^(3a) isindependently —OC(O)R. In some embodiments, R² and R^(3a) isindependently —OC(O)NR₂. In some embodiments, R² and R^(3a) isindependently —OP(O)R₂. In some embodiments, R² and R^(3a) isindependently —OP(O)(OR)₂. In some embodiments, R² and R^(3a) isindependently —OP(O)(OR)NR₂. In some embodiments, R² and R^(3a) isindependently —OP(O)(NR₂)₂—. In some embodiments, R² and R^(3a) isindependently —N(R)C(O)OR. In some embodiments, R² and R^(3a) isindependently —N(R)C(O)R. In some embodiments, R² and R^(3a) isindependently —N(R)C(O)NR₂. In some embodiments, R² and R^(3a) isindependently —NP(O)R₂. In some embodiments, R² and R^(3a) isindependently —N(R)P(O)(OR)₂. In some embodiments, R² and R^(3a) isindependently —N(R)P(O)(OR)NR₂. In some embodiments, R² and R^(3a) isindependently —N(R)P(O)(NR₂)₂. In some embodiments, R² and R^(3a) isindependently —N(R)S(O)₂R.

In some embodiments, R² and R^(3a) is independently —OH. In someembodiments, R² and R^(3a) is independently —NH₂. In some embodiments,R² and R^(3a) is independently —CH₂NH₂. In some embodiments, R² andR^(3a) is independently —CH₂NHCOMe. In some embodiments, R² and R^(3a)is independently —CH₂NHCONHMe. In some embodiments, R² and R^(3a) isindependently —NHCOMe. In some embodiments, R² and R^(3a) isindependently —NHCONHEt. In some embodiments, R² and R^(3a) isindependently —SiMe₃. In some embodiments, R² and R^(3a) isindependently —SiMe₂OH. In some embodiments, R² and R^(3a) isindependently —SiMe(OH)₂. In some embodiments R² and R^(3a) isindependently

In some embodiments, R² and R^(3a) is independently Br. In someembodiments, R² and R^(3a) is independently Cl. In some embodiments, R²and R^(3a) is independently F. In some embodiments, R² and R^(3a) isindependently Me. In some embodiments, R² and R^(3a) is independently—NHMe. In some embodiments, R² and R^(3a) is independently —NMe₂. Insome embodiments, R² and R^(3a) is independently —NHCO₂Et. In someembodiments, R² and R^(3a) is independently —CN. In some embodiments, R²and R^(3a) is independently —CH₂Ph. In some embodiments, R² and R^(3a)is independently —NHCO₂tBu. In some embodiments, R² and R^(3a) isindependently —CO₂ ^(t)Bu. In some embodiments, R² and R^(3a) isindependently —OMe. In some embodiments, R² and R^(3a) is independently—CF₃.

In some embodiments, R² or R^(3a) is selected from those depicted inTable 1 below.

As defined above and described herein, R³ is hydrogen, deuterium,halogen, —CN, —NO₂, —OR, —NR₂, —SR, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R,—C(O)OR, —C(O)NR₂, —C(O)NR(OR), —OC(O)R, —OC(O)NR₂, —OP(O)(OR)₂,—OP(O)(NR₂)₂, —OP(O)(OR)NR₂, —N(R)C(O)R, N(R)C(O)OR, —N(R)C(O)NR₂,—N(R)S(O)₂R, —N(R)S(O)₂NR₂, —N(R)P(O)(OR)₂, —N(R)P(O)(OR)NR₂,—P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R, —Si(OH)(R)₂, or—Si(R)₃.

In some embodiments, R³ is hydrogen. In some embodiments, R³ isdeuterium. In some embodiments, R³ is halogen. In some embodiments, R³is —CN. In some embodiments, R³ is —NO₂. In some embodiments, R³ is —OR.In some embodiments, R³ is —NR₂. In some embodiments, R³ is —SR. In someembodiments, R³ is —S(O)₂R. In some embodiments, R³ is —S(O)₂NR₂. Insome embodiments, R³ is —S(O)R. In some embodiments, R³ is —C(O)R. Insome embodiments, R³ is —C(O)OR. In some embodiments, R³ is —C(O)NR₂. Insome embodiments, R³ is —C(O)NR(OR). In some embodiments, R³ is —OC(O)R.In some embodiments, R³ is —OC(O)NR₂. In some embodiments, R³ is—OP(O)(OR)₂. In some embodiments, R³ is —OP(O)(NR₂)₂. In someembodiments, R³ is —OP(O)(OR)NR₂. In some embodiments, R³ is —N(R)C(O)R.In some embodiments, R³ is —N(R)C(O)OR. In some embodiments, R³ is—N(R)C(O)NR₂. In some embodiments, R³ is —N(R)S(O)₂R. In someembodiments, R³ is —N(R)S(O)₂NR₂. In some embodiments, R³ is—N(R)P(O)(OR)₂. In some embodiments, R³ is —N(R)P(O)(OR)NR₂. In someembodiments, R³ is —P(O)(OR)₂. In some embodiments, R³ is —P(O)(NR₂)OR.In some embodiments, R³ is —P(O)(NR₂)₂. In some embodiments, R³ is—Si(OH)₂R. In some embodiments, R³ is —Si(OH)(R)₂. In some embodiments,R³ is —Si(R)₃.

In some embodiments, R³ is methyl. In some embodiments, R³ is —OCH₃. Insome embodiments, R³ is chloro.

In some embodiments, R³ is selected from those depicted in Table 1.

As defined above and described herein, each R⁴ is independentlyhydrogen, deuterium, —R⁶, halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R,—S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R,—OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, —N(R)S(O)₂R,—P(O)(OR)₂, —P(O)(NR₂)OR, or —P(O)(NR₂)₂.

In some embodiments, R⁴ is hydrogen. In some embodiments, R⁴ is —R⁶. Insome embodiments, R⁴ is halogen. In some embodiments, R⁴ is —CN. In someembodiments, R⁴ is —NO₂. In some embodiments, R⁴ is —OR. In someembodiments, R⁴ is —SR. In some embodiments, R⁴ is —NR₂. In someembodiments, R⁴ is —S(O)₂R. In some embodiments, R⁴ is —S(O)₂NR₂. Insome embodiments, R⁴ is —S(O)R. In some embodiments, R⁴ is —C(O)R. Insome embodiments, R⁴ is —C(O)OR. In some embodiments, R⁴ is —C(O)NR₂. Insome embodiments, R⁴ is —C(O)N(R)OR. In some embodiments, R⁴ is —OC(O)R.In some embodiments, R⁴ is —OC(O)NR₂. In some embodiments, R⁴ is—N(R)C(O)OR. In some embodiments, R⁴ is —N(R)C(O)R. In some embodiments,R⁴ is —N(R)C(O)NR₂. In some embodiments, R⁴ is —N(R)S(O)₂R. In someembodiments, R⁴ is —P(O)(OR)₂. In some embodiments, R⁴ is —P(O)(NR₂)OR.In some embodiments, R⁴ is —P(O)(NR₂)₂.

In some embodiments, R⁴ is methyl. In some embodiments, R⁴ is ethyl. Insome embodiments, R⁴ is cyclopropyl.

In some embodiments, R⁴ is selected from those depicted in Table 1.

As defined above and described herein, R⁵ is hydrogen, deuterium, anoptionally substitute C₁₋₄ aliphatic, or —CN.

In some embodiments, R⁵ is hydrogen. In some embodiments, R⁵ isdeuterium. In some embodiments, R⁵ is an optionally substituted C₁₋₄aliphatic. In some embodiments, R⁵ is —CN.

In some embodiments, R⁵ is selected from those depicted in Table 1.

As defined above and described herein, each R⁶ is independently anoptionally substituted group selected from C₁₋₆ aliphatic, phenyl, a 4-7membered saturated or partially unsaturated heterocyclic ring having 1-3heteroatoms independently selected from boron, nitrogen, oxygen,silicon, and sulfur, and a 5-6 membered heteroaryl ring having 1-4heteroatoms independently selected from boron, nitrogen, oxygen,silicon, and sulfur.

In some embodiments, R⁶ is an optionally substituted C₁₋₆ aliphatic. Insome embodiments, R⁶ is an optionally substituted phenyl. In someembodiments, R⁶ is an optionally substituted 4-7 membered saturated orpartially unsaturated heterocyclic ring having 1-3 heteroatomsindependently selected from boron, nitrogen, oxygen, silicon, andsulfur. In some embodiments, R⁶ is an optionally substituted 5-6membered heteroaryl ring having 1-4 heteroatoms independently selectedfrom boron, nitrogen, oxygen, silicon, and sulfur.

In some embodiments, R⁶ is selected from those depicted in Table 1.

As defined generally above, each R⁷ is independently hydrogen,deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R, —N(R)₂, —P(O)(R)₂,—P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)R₂, —Si(OH)₂R, —SiR₃, oran optionally substituted C₁₋₄ aliphatic, or R¹ and X¹ or X³ are takentogether with their intervening atoms to form a 5-7 membered saturated,partially unsaturated, carbocyclic ring or heterocyclic ring having 1-3heteroatoms, independently selected from boron, nitrogen, oxygen,silicon, or sulfur, or two R⁷ groups on the same carbon are optionallytaken together with their intervening atoms to form a 3-6 membered spirofused ring or a 4-7 membered heterocyclic ring having 1-2 heteroatomsindependently selected from boron, nitrogen, oxygen, silicon, or sulfur,or two R⁷ groups on adjacent carbon atoms are optionally taken togetherwith their intervening atoms to form a 3-7 membered saturated, partiallyunsaturated, carbocyclic ring or heterocyclic ring having 1-3heteroatoms independently selected from boron, nitrogen, oxygen,silicon, or sulfur, or a 7-13 membered saturated, partially unsaturated,bridged heterocyclic ring, or a spiro heterocyclic ring having 1-3heteroatoms, independently selected from boron, nitrogen, oxygen,silicon, or sulfur.

In some embodiments, R⁷ is hydrogen. In some embodiments, R⁷ isdeuterium. In some embodiments, R⁷ is halogen. In some embodiments, R⁷is —CN. In some embodiments, R⁷ is —OR. In some embodiments, R⁷ is —SR.In some embodiments, R⁷ is —S(O)R. In some embodiments, R⁷ is —S(O)₂R.In some embodiments, R⁷ is —NR₂. In some embodiments, R⁷ is —Si(R)₃. Insome embodiments, R⁷ is —P(O)(R)₂. In some embodiments, R⁷ is—P(O)(OR)₂. In some embodiments, R⁷ is —P(O)(NR₂)OR. In someembodiments, R⁷ is —P(O)(NR₂)₂. In some embodiments, R⁷ is —Si(OH)R₂. Insome embodiments, R⁷ is —Si(OH)₂R. In some embodiments, R⁷ is anoptionally substituted C₁₋₄ aliphatic. In some embodiments, R⁷ and X¹ orX³ are taken together with their intervening atoms to form a 5-7membered saturated, partially unsaturated, carbocyclic ring orheterocyclic ring having 1-3 heteroatoms, independently selected fromboron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, two R⁷groups on the same carbon are optionally taken together with theirintervening atoms to form a 3-6 membered spiro fused ring or a 4-7membered heterocyclic ring having 1-2 heteroatoms independently selectedfrom boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments,two R⁷ groups on adjacent carbon atoms are optionally taken togetherwith their intervening atoms to form a 3-7 membered saturated, partiallyunsaturated, carbocyclic ring or heterocyclic ring having 1-3heteroatoms independently selected from boron, nitrogen, oxygen,silicon, or sulfur. In some embodiments, two R⁷ groups on adjacentcarbon atoms are optionally taken together with their intervening atomsto form a 7-13 membered saturated, partially unsaturated, bridgedheterocyclic ring, or a spiro heterocyclic ring having 1-3 heteroatoms,independently selected from boron, nitrogen, oxygen, silicon, or sulfur.

In some embodiments, R⁷ is selected from hydrogen, halogen, —CN, —OR,—NR₂, or C₁₋₄ alkyl. In some embodiments, R⁷ is selected from hydrogen,halogen, —CN, or C₁₋₄ alkyl. In some embodiments, R⁷ is fluoro. In someembodiments, two R⁷ groups on the same carbon are optionally takentogether with their intervening atoms to form a 3- or 4-membered spirofused ring.

In some embodiments, R⁷ is selected from those depicted in Table 1below.

As defined above and described herein, Ring A is a bi- or tricyclic ringselected from

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is selected from those depicted in Table 1below.

As defined above and described herein, Ring B is a fused ring selectedfrom 6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 5 to 7-memberedsaturated or partially unsaturated carbocyclyl, 5 to 7-memberedsaturated or partially unsaturated heterocyclyl with 1-3 heteroatomsindependently selected from boron, nitrogen, oxygen, silicon, or sulfur,or 5-membered heteroaryl with 1-4 heteroatoms independently selectedfrom nitrogen, oxygen or sulfur;

In some embodiments, Ring B is a fused 6-membered aryl. In someembodiments, Ring B is a fused 6-membered heteroaryl containing 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, Ring B is a fused 5 to 7-membered saturated orpartially unsaturated carbocyclyl. In some embodiments, Ring B is fused5 to 7-membered saturated or partially saturated heterocyclyl with 1-3heteroatoms independently selected from boron, nitrogen, oxygen,silicon, or sulfur. In some embodiments, Ring B is fused 5-memberedheteroaryl with 1-4 heteroatoms independently selected from boron,nitrogen, oxygen, silicon, or sulfur.

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, each Ring B is

In some embodiments, each Ring B is

In some embodiments, each Ring B is

In some embodiments, each Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is selected from those depicted in Table 1below.

As defined above and described herein, Ring C is a mono- or bicyclicring selected from

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments. Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is a mono- or bicyclic ring selected from

In some embodiments, Ring C is selected from those depicted in Table 1below.

As defined above and described herein, Ring D is a ring selected from 6to 10-membered aryl or heteroaryl containing 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 5 to 7-memberedsaturated or partially unsaturated carbocyclyl, 5 to 7-memberedsaturated or partially unsaturated heterocyclyl with 1-3 heteroatomsindependently selected from boron, nitrogen, oxygen, silicon, or sulfur,or 5-membered heteroaryl with 1-4 heteroatoms independently selectedfrom nitrogen, oxygen or sulfur;

In some embodiments, Ring D is a 6-membered aryl. In some embodiments,Ring D is a 6-membered heteroaryl containing 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, Ring D is a 5 to 7-membered saturated or partiallyunsaturated carbocyclyl. In some embodiments, Ring D is 5 to 7-memberedsaturated or partially saturated heterocyclyl with 1-3 heteroatomsindependently selected from boron, nitrogen, oxygen, silicon, or sulfur.In some embodiments, Ring D is 5-membered heteroaryl with 1-4heteroatoms independently selected from boron, nitrogen, oxygen,silicon, or sulfur.

In some embodiments, Ring D is isoquinoline. In some embodiments, Ring Dis imidazo[1,2-a]pyridine.

In some embodiments, Ring D is selected from those depicted in Table 1below.

As defined above and described herein, each of Ring E, Ring F, and RingG is independently a fused ring selected from 6-membered aryl,6-membered heteroaryl containing 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 5 to 7-membered saturated or partiallyunsaturated carbocyclyl, 5 to 7-membered saturated or partiallyunsaturated heterocyclyl with 1-3 heteroatoms independently selectedfrom boron, nitrogen, oxygen, silicon, or sulfur, or 5-memberedheteroaryl with 1-4 heteroatoms independently selected from nitrogen,oxygen or sulfur.

In some embodiments, each of Ring E, Ring F, and Ring G is independentlya fused ring selected from 6-membered aryl. In some embodiments, each ofRing E, Ring F, and Ring G is independently a fused ring selected from6-membered heteroaryl containing 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. In some embodiments, each of Ring E,Ring F, and Ring G is independently a fused ring selected from a 5 to7-membered saturated or partially unsaturated carbocyclyl. In someembodiments, each of Ring E, Ring F, and Ring G is independently a fusedring selected from a 5 to 7-membered saturated or partially unsaturatedheterocyclyl with 1-3 heteroatoms independently selected from boron,nitrogen, oxygen, silicon, or sulfur. In some embodiments, each of RingE, Ring F, and Ring G is independently a fused ring selected from a5-membered heteroaryl with 1-4 heteroatoms independently selected fromnitrogen, oxygen or sulfur.

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

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In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments. Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, each of Ring E and Ring G is independently

In some embodiments, each of Ring E and Ring G is independently

In some embodiments, each of Ring E and Ring G is independently

In some embodiments, each of Ring E and Ring G is independently

In some embodiments, each of Ring E and Ring G is independently

In some embodiments, each of Ring E and Ring G is independently is

In some embodiments, each of Ring E and Ring G is independently

In some embodiments, each of Ring E and Ring G is independently

In some embodiments, each of Ring E and Ring G is independently

In some embodiments, each of Ring E and Ring G is independently

In some embodiments, each of Ring E and Ring G is independently

In some embodiments, each of Ring E and Ring G is independently

In some embodiments, each of Ring E and Ring G is independently

In some embodiments, each of Ring E and Ring G is independently

In some embodiments, each of Ring E and Ring G is independently

In some embodiments, each of Ring E and Ring G is independently

In some embodiments, each of Ring E and Ring G is independently

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiment, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is selected from thosedepicted in Table 1, below.

As defined above and described herein, Ring H is a ring selected from a7-9 membered saturated or partially unsaturated carbocyclyl orheterocyclyl ring with 1-3 heteroatoms independently selected fromboron, nitrogen, oxygen, silicon, or sulfur, wherein Ring E isoptionally further substituted with 1-2 oxo groups.

In some embodiments, Ring H is a ring selected from a 7-9 memberedsaturated or partially unsaturated carbocyclyl or heterocyclyl ring with1-3 heteroatoms independently selected from boron, nitrogen, oxygen,silicon, or sulfur, wherein Ring H is optionally further substitutedwith 1-2 oxo groups.

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

some embodiments, Ring H is

In some embodiments. Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is selected from those depicted in Table 1,below.

In some embodiments, Ring E and Ring H is

As defined above and described herein, each of Ring I and Ring J isindependently a fused ring selected from 6-membered aryl, 6-memberedheteroaryl containing 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, 5 to 7-membered saturated or partiallyunsaturated carbocyclyl, 5 to 7-membered saturated or partiallyunsaturated heterocyclyl with 1-3 heteroatoms independently selectedfrom boron, nitrogen, oxygen, silicon, or sulfur, or 5-memberedheteroaryl with 1-4 heteroatoms independently selected from nitrogen,oxygen or sulfur

In some embodiments, each of Ring I and Ring J is independently a6-membered aryl. In some embodiments, each of Ring I and Ring J isindependently a 6-membered heteroaryl containing 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, each of Ring I and Ring J is independently a 5 to7-membered saturated or partially unsaturated carbocyclyl. In someembodiments, each of Ring I and Ring J is independently a 5 to7-membered saturated or partially unsaturated heterocyclyl with 1-3heteroatoms independently selected from boron, nitrogen, oxygen,silicon, or sulfur. In some embodiments, each of Ring I and Ring J isindependently a 5-membered heteroaryl with 1-3 heteroatoms independentlyselected from nitrogen, oxygen or sulfur.

In some embodiments, each of Ring I and Ring J is independently

In some embodiments, each of Ring I and Ring J is independently

In some embodiments, each of Ring I and Ring J is independently

In some embodiments, each of Ring I and Ring J is independently

In some embodiments, each of Ring I and Ring J is independently

In some embodiments, Ring I and Ring J is independently is

In some embodiments, Ring I and Ring J is independently

In some embodiments, Ring I and Ring J is independently

In some embodiments, Ring I and Ring J is selected from those depictedin Table 1, below.

As defined above and described herein, Ring K is a fused ring selectedfrom a 7-12 membered saturated or partially unsaturated carbocyclyl orheterocyclyl with 1-3 heteroatoms independently selected from boron,nitrogen, oxygen, silicon, or sulfur, wherein Ring H is optionallyfurther substituted with 1-2 oxo groups.

In some embodiments, Ring K is a fused ring selected from a 7-12membered saturated or partially unsaturated carbocyclyl. In someembodiments, Ring K is a 7-12 membered saturated or partiallyunsaturated heterocyclyl ring with 1-3 heteroatoms independentlyselected from boron, nitrogen, oxygen, silicon, or sulfur. In someembodiments, Ring K is optionally further substituted with 1-2 oxogroups.

In some embodiments, Ring K is

In some embodiments, Ring K is

In some embodiments, Ring K is

In some embodiments, Ring K is

In some embodiments, Ring K is

In some embodiments, Ring K is

In some embodiments, Ring K is

In some embodiments, Ring K is

In some embodiments, Ring K is

some embodiments, Ring K is

In some embodiments, Ring K is

In some embodiments, Ring K is

In some embodiments, Ring K is

In some embodiments, Ring K is

In some embodiments, Ring K is

In some embodiments, Ring K is selected from those depicted in Table 1below.

In some embodiments, Ring I, Ring J, and Ring K is

As defined above and described herein, Ring M is selected from

In some embodiments, Ring M is

In some embodiments, Ring M is

In some embodiments, Ring M is

In some embodiments, Ring M is

In some embodiments, Ring M is

In some embodiments, Ring M is

In some embodiments, Ring M is

In some embodiments, Ring M is

In some embodiments, Ring M is

In some embodiments, Ring M is

In some embodiments, Ring M is

In some embodiments, Ring M is selected from those depicted in Table 1below.

As defined above and described here, L¹ is a covalent bond or a C₁₋₃bivalent straight or branched saturated or unsaturated hydrocarbon chainwherein 1-2 methylene units of the chain are independently andoptionally replaced with —O—, —C(O)—, —C(S)—, —C(R)₂—, —CH(R)—, —C(F)₂—,—N(R)—, —S—, —S(O)₂— or —(C)═CH—;

In some embodiments, L¹ is a covalent bond. In some embodiments, L¹ is aC₁₋₃ aliphatic. In some embodiments, L¹ is —CH₂—. In some embodiments,L¹ is —C(D)(H)—. In some embodiments, L¹ is —C(D)₂-. In someembodiments, L¹ is —CH₂CH₂—. In some embodiments, L¹ is —NR—. In someembodiments, L¹ is —CH₂NR—. In some embodiments, L¹ is or —O—. In someembodiments, L¹ is —CH₂O—. In some embodiments, L¹ is —S—. In someembodiments, L¹ is —OC(O)—. In some embodiments, L¹ is —C(O)O—. In someembodiments, L¹ is —C(O)—. In some embodiments, L¹ is —S(O)—. In someembodiments, L¹ is —S(O)₂—. In some embodiments, L¹ is —NRS(O)₂—. Insome embodiments, L¹ is —S(O)₂NR—. In some embodiments, L¹ is —NRC(O)—.In some embodiments, L¹ is —C(O)NR—.

In some embodiments, L¹ is selected from those depicted in Table 1below.

As defined above and described herein,

is a single or double bond.

In some embodiments,

is a single bond. In some embodiments,

is a double bond.

In some embodiments,

is selected from those depicted in Table 1 below.

As defined above and described herein, m is 0, 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, or 16.

In some embodiments, m is 0. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 3. In some embodiments, mis 4. In some embodiments, m is 5. In some embodiments, m is 6. In someembodiments, m is 7. In some embodiments, m is 8. In some embodiments, mis 9. In some embodiments, m is 10. In some embodiments, m is 11. Insome embodiments, m is 12. In some embodiments, m is 13. In someembodiments, m is 14. In some embodiments, m is 15. In some embodiments,m is 16.

In some embodiments, m is selected from those depicted in Table 1 below.

As defined above and described herein, n is 0, 1, 2, 3 or 4.

In some embodiments, n is 0. In some embodiments, n is 1. In someembodiments, n is 2. In some embodiments, n is 3. In some embodiments, nis 4.

In some embodiments, n is selected from those depicted in Table 1 below.

As defined above and described herein, p is 0 or 1.

In some embodiments, p is 0. In some embodiments, p is 1.

In some embodiments, p is selected from those depicted in Table 1 below.

As defined above and described herein, q is 0, 1, 2, 3 or 4.

In some embodiments, q is 0. In some embodiments, q is 1. In someembodiments, q is 2. In some embodiments, q is 3. In some embodiments, qis 4.

In some embodiments, q is selected from those depicted in Table 1 below.

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is selected from those in Table 1 below.

In some embodiments, the present invention provides a compound offormula I-a, wherein LBM is

as shown, to provide a compound of formula I-a-6:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,L, L¹, R¹, R², X¹, X², X³, m, X, L^(x), Ring T, R^(x), R^(y), x, and yis as defined above and described in embodiments herein, both singly andin combination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and LBM is

as shown, to provide a compound of formula I-a-7:

or a pharmaceutically acceptable salt thereof, wherein each of L, R², m,X, L^(x), Ring T, R^(x), R^(y), x, and y is as defined above anddescribed in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and LBM is

as shown, to provide a compound of formula I-a-8:

or a pharmaceutically acceptable salt thereof, wherein each of DIM, L,R², m, X, L^(x), Ring T, R^(x), R^(y), x, and y is as defined above anddescribed in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and LBM is

as shown, to provide a compound of formula I-a-9:

or a pharmaceutically acceptable salt thereof, wherein each of DIM, L,X, R², m, L^(x), Ring T, R^(x), R^(y), x, and y is as defined above anddescribed in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and LBM is

as shown, to provide a compound of formula I-a-10:

or a pharmaceutically acceptable salt thereof, wherein each of Ring C,Ring D, L, L¹, R¹, R², R^(3a), X¹, X², X³, m, n, X, L^(x), Ring T,R^(x), R^(y), x, and y is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and LBM is

as shown, to provide a compound of formula I-a-11:

or a pharmaceutically acceptable salt thereof, wherein each of DIM, L,X, L^(x), Ring T, R^(x), R^(y), x, and y is as defined above anddescribed in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and LBM is

as shown, to provide a compound of formula I-a-12:

or a pharmaceutically acceptable salt thereof, wherein each of Ring E,Ring F, Ring G, L, L¹, R¹, R², X¹, X², X³, m, X, L^(x), Ring T, R^(x),R^(y), x, and y is as defined above and described in embodiments herein,both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and LBM is

as shown, to provide a compound of formula I-a-13:

or a pharmaceutically acceptable salt thereof, wherein each of DIM, L,X, R², L^(x), Ring T, R^(x), R^(y), m, x, and y is as defined above anddescribed in embodiments herein, both singly and in combination.

As shown above a generally described herein, a core structure depictedas

includes for example without limitation, structures

In some embodiments, the present invention provides a compound offormula I-a, wherein LBM is

as shown, to provide a compound of formula I-a-44:

or a pharmaceutically acceptable salt thereof, wherein each of Ring M,Ring D, L, L¹, R^(3a), R⁷, n, q, X, L^(x), Ring T, R^(x), R^(y), x, andy is as defined above and described in embodiments herein, both singlyand in combination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and LBM is

as shown, to provide a compound of formula I-a-45:

or a pharmaceutically acceptable salt thereof, wherein each of L,R^(3a), n, X, L^(x), Ring T, R^(x), R^(y), x, and y is as defined aboveand described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and LBM is

as shown, to provide a compound of formula I-a-46:

or a pharmaceutically acceptable salt thereof, wherein each of L,R^(3a), n, X, L^(x), Ring T, R^(x), R^(y), x, and y is as defined aboveand described in embodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-uu:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein each ofthe variables A, B, C, W, X, Y, and Z is as described and defined inU.S. Pat. No. 5,721,246, the entirety of each of which is hereinincorporated by reference.

In some embodiments, LBM is a IAP E3 Ubiquitin ligase binding moietyrecited in Varfolomeev, E. et al., IAP Antagonists InduceAutoubiquitination of c-IAPs, NF-κB activation, and TNFα-DependentApoptosis, Cell, 2007, 131(4): 669-81, such as, for example:

wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is a VHL E3 ubiquitin ligase binding moietythereby forming a compound of formula I-ww-1,1-ww-2,1-ww-3,1-ww-4, orI-ww-5 respectively:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein each ofthe variables R¹, R², R³, X, and X′ is as defined and described in WO2013/106643 and US 2014/0356322, the entirety of each of which is hereinincorporated by reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is a VHL E3 ubiquitin ligase binding moietythereby forming a compound of formula I-xx-1,1-xx-2, I-xx-3,1-xx-4,T-xx-5 or I-xx-6 respectively:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein each ofthe variables R¹, R², R³, R₅, R₅, R₇, R₉, R₁₀, R₁₁, R₁₄, R₁₅, R₁₆, R₁₇,R₂₃, R₂₅, E, G, M, X, X′, Y, Z₁, Z₂, Z₃, Z₄, and o is as defined anddescribed in WO 2016/149668 and US 2016/0272639, the entirety of each ofwhich is herein incorporated by reference.

As used herein, depiction of brackets around any LBM

means that the

moiety is covalently attached to said LBM at any available modifiablecarbon, nitrogen, oxygen, or sulfur atom. For purposes of clarity and byway of example, such available modifiable carbon, nitrogen, oxygen, orsulfur atoms in the following LBM compound structure are depicted below,wherein each wavy bond defines the point of attachment to said

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is a VHL E3 ubiquitin ligase binding moietythereby forming a compound of formula I-yy-1,1-yy-2, or I-yy-3respectively:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein each ofthe variables R^(p), R₉, R₁₀, R₁₁, R_(14a), R_(14b), R₁₅, R₁₆, W³, W⁴,W⁵, X¹, X², and o is as defined and described in WO 2016/118666 and US2016/0214972, the entirety of each of which is herein incorporated byreference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is VHL E3 ubiquitin ligase binding moiety therebyforming a compound of formula I-zz-1,1-zz-2, or I-zz-3 respectively:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein each ofthe variables A¹, A², A³, R⁵, G and Z is as defined and described in WO2017/176958.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is a MDM2 (i.e. human double minute 2 or HDM2) E3ligase binding moiety thereby forming a compound of formula I-aaa-1,I-aaa-2, I-aaa-3, I-aaa-4, I-aaa-5, I-aaa-6, I-aaa-7, I-aaa-8, I-aaa-9,I-aaa-10, I-aaa-11, I-aaa-12, I-aaa-13, I-aaa-14, I-aaa-15, I-aaa-16,I-aaa-17, or I-aaa-18 respectively:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein each ofthe variables R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃,R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇,R₂₈, Rr, R₂, R₃, R_(4′), R_(5′), R_(6′), R_(7′), R_(8′), R_(9′),R_(10′), R_(11′), R_(12′), R_(1″), A, A′, A″, X, Y, and Z is as definedand described in WO 2017/011371 and US 2017/008904, the entirety of eachof which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an IAP E3 ubiquitin ligase binding moietythereby forming a compound of formula I-bbb-1, I-bbb-2,1-bbb-3, orI-bbb-4 respectively:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein each ofthe variables R¹, R², R³, R⁴, R⁵, R⁶, and R⁷, is as defined anddescribed in WO 2017/011590 and US 2017/0037004, the entirety of each ofwhich is herein incorporated by reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety, a DCAF15 E3 ubiquitin ligase binding moiety, or a VHL E3ubiquitin ligase binding moiety; thereby forming a compound of formulaI-ccc-1 or I-ccc-2:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK is asdefined above and described in embodiments herein, and wherein:

-   each of X^(4a) and X^(5a) is independently a bivalent moiety    selected from —CH₂—, —C(O)—, —C(S)—, or

-   each of R^(3b) and R^(4a) is independently hydrogen, —R⁶, halogen,    —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R,    —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,    —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;-   R^(5a) is hydrogen or C₁₋₆ aliphatic;-   each R⁶ is independently an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, and a 5-6 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur;-   Ring B^(a) is selected from 6-membered aryl containing 0-2 nitrogen    atoms or a 8-10 membered bicyclic heteroaryl having 1-5 heteroatoms    independently selected from nitrogen, oxygen, or sulfur;-   Ring C^(a) is a selected from 6-membered aryl containing 0-2    nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms    independently selected from nitrogen, oxygen or sulfur;-   o is 0, 1, 2, 3 or 4;-   q is 0, 1, 2, 3 or 4; and-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are optionally taken together        with their intervening atoms to form a 4-7 membered saturated,        partially unsaturated, or heteroaryl ring having 0-3        heteroatoms, in addition to the nitrogen, independently selected        from nitrogen, oxygen, and sulfur.

As defined above and described herein, each of X^(4a) and X^(5a) isindependently a bivalent moiety selected from —CH₂—, —C(O)—, —C(S)—, or

In some embodiments, X^(4a) is —CH₂—, —C(O)—, —C(S)—, or

In some embodiments, X^(4a) is selected from those depicted in Table 1,below.

In some embodiments, X^(5a) is —CH₂—, —C(O)—, —C(S)—, or

In some embodiments, X^(5a) is selected from those depicted in Table 1,below.

As defined above and described herein, each of R^(3b) and R^(4a) isindependently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR, —SR, —NR₂,—S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR,—OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, or—N(R)S(O)₂R.

In some embodiments, R^(3b) is hydrogen, —R⁶, halogen, —CN, —NO₂, —OR,—SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, C(O)NR₂,—C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,or —N(R)S(O)₂R.

In some embodiments, R^(3b) is methyl.

In some embodiments, R^(3b) is selected from those depicted in Table 1,below.

In some embodiments, R^(4a) is hydrogen, —R⁶, halogen, —CN, —NO₂, —OR,—SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, C(O)NR₂,—C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,or —N(R)S(O)₂R.

In some embodiments, R^(4a) is methyl.

In some embodiments, R^(4a) is selected from those depicted in Table 1,below.

As defined above and described herein, R^(5a) is hydrogen or C₁₋₆aliphatic.

In some embodiments, R^(5a) is t-butyl.

In some embodiments, R^(5a) is selected from those depicted in Table 1,below.

As defined above and described herein, each R⁶ is independently anoptionally substituted group selected from C₁₋₆ aliphatic, phenyl, a 4-7membered saturated or partially unsaturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur,and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur.

In some embodiments, R⁶ is an optionally substituted C₁₋₆ aliphaticgroup. In some embodiments, R⁶ is an optionally substituted phenyl. Insome embodiments, R⁶ is an optionally substituted 4-7 membered saturatedor partially unsaturated heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, R⁶ is an optionally substituted 5-6 membered heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur.

In some embodiments, R⁶ is selected from those depicted in Table 1,below.

As defined above and described herein, Ring B^(a) is selected from6-membered aryl containing 0-2 nitrogen atoms or a 8-10 memberedbicyclic heteroaryl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

In some embodiments, Ring B^(a) is a 6-membered aryl containing 0-2nitrogen atoms. In some embodiments, Ring B^(a) is a 8-10 memberedbicyclic heteroaryl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

In some embodiments, Ring B^(a) is

In some embodiments, Ring B^(a) is selected from those depicted in Table1, below.

As defined above and described herein, Ring C^(a) is selected from6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroarylwith 1-3 heteroatoms independently selected from nitrogen, oxygen orsulfur.

In some embodiments, Ring C^(a) is a 6-membered aryl containing 0-2nitrogen atoms. In some embodiments, Ring C^(a) is a 5-memberedheteroaryl with 1-3 heteroatoms independently selected from nitrogen,oxygen or sulfur.

In some embodiments, Ring C^(a) is

In some embodiments, Ring C^(a) is selected from those depicted in Table1, below.

In some embodiments, o is selected from those depicted in Table 1,below.

As defined above and described herein, o is 0, 1, 2, 3 or 4.

In some embodiments, o is 0. In some embodiments, o is 1. In someembodiments, o is 2. In some embodiments, o is 3. In some embodiments, ois 4.

In some embodiments, o is selected from those depicted in Table 1,below.

As defined above and described herein, q is 0, 1, 2, 3 or 4.

In some embodiments, q is 0. In some embodiments, q is 1. In someembodiments, q is 2. In some embodiments, q is 3. In some embodiments, qis 4.

In some embodiments, q is selected from those depicted in Table 1,below.

As defined above and described herein, each R is independently hydrogen,or an optionally substituted group selected from C₁₋₆ aliphatic, phenyl,a 4-7 membered saturated or partially unsaturated heterocyclic having1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, or: two Rgroups on the same nitrogen are optionally taken together with theirintervening atoms to form a 4-7 membered saturated, partiallyunsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition tothe nitrogen, independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R is hydrogen. In some embodiments, R is phenyl. Insome embodiments, R is a 4-7 membered saturated or partially unsaturatedheterocyclic having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, R is a 5-6 memberedheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, two R groups on thesame nitrogen are optionally taken together with their intervening atomsto form a 4-7 membered saturated, partially unsaturated, or heteroarylring having 0-3 heteroatoms, in addition to the nitrogen, independentlyselected from nitrogen, oxygen, and sulfur.

In some embodiments, R is selected from those depicted in Table 1,below.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a VHL binding moiety thereby forming acompound of formula I-ddd:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein each ofthe variables R₉, R₁₀, R₁₁, R_(14a), and R₁₅ is as described and definedin WO 2017/030814, WO 2016/118666, and US 2017/0327469, the entirety ofeach of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a VHL binding moiety thereby forming acompound of formula I-eee-1 or I-eee-2:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein each ofthe variables X, W, R₉, R₁₀, R₁₁, R_(14a), and R_(14b), R₁₅, R¹⁶, and ois as described and defined in WO 2017/030814, WO 2016/118666, and US2017/0327469, the entirety of each of which is herein incorporated byreference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is an IAP binding moiety thereby forming acompound of formula I-fff:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein each ofthe variables W, Y, Z, R¹, R², R³, R⁴, and R⁵ is as described anddefined in WO 2014/044622, US 2015/0225449. WO 2015/071393, and US2016/0272596, the entirety of each of which is herein incorporated byreference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a MDM2 binding moiety thereby forming acompound of formula I-ggg:

or a pharmaceutically acceptable salt thereof, wherein U and IRAK are asdefined above and described in embodiments herein, as described anddefined in Hines, J. et al., Cancer Res. (DOI:10.1158/0008-5472.CAN-18-2918), the entirety of each of which is hereinincorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a DCAF16 binding moiety thereby forming acompound of formula I-hhh:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, as described anddefined in Zhang, X. et al., bioRxiv (doi:https://doi.org/10.1101/443804), the entirety of each of which is hereinincorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a RNF114 binding moiety thereby forming acompound of formula I-iii:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, as described anddefined in Spradin, J. N. et al., bioRxiv (doi:https://doi.org/10.1101/436998), the entirety of each of which is hereinincorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a RNF4 binding moiety thereby forming acompound of formula I-jjj:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, as described anddefined in Ward, C. C., et al., bioRxiv (doi:https://doi.org/10.1101/439125), the entirety of each of which is hereinincorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a VHL binding moiety thereby forming acompound of formula I-nnn-1 or I-nnn-2:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein each ofthe variables R¹, R², R³, X, and Y is as defined and described in WO2019/084026, the entirety of each of which is herein incorporated byreference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a VHL binding moiety thereby forming acompound of formula I-ooo-1 or I-ooo-2:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein each ofthe variables R¹, R³, and Y is as defined and described in WO2019/084030, the entirety of each of which is herein incorporated byreference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-ppp-1, I-PPP-2,1-PPP-3,or I-ppp-4:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described herein, and wherein each of the variablesR⁴, R¹⁰, R¹¹, R¹⁵, R¹⁶, R¹⁷, W¹, W², and X is as defined in WO2019/099868 which is herein incorporated by reference in its entirety,and wherein

is attached to R¹⁷ or R¹⁶ at the site of attachment of R¹² as defined inWO 2018/237026, such that

takes the place of the R¹² substituent.

In some embodiments LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

As defined herein and described below, wherein a formula is depictedusing square brackets, e.g.,

L is attached to a modifiable carbon, oxygen, or nitrogen atom withinDIM or LBM including substitution or replacement of a defined group inDIM or LBM.

In some embodiments, the present invention provides a compound offormula I-a, wherein LBM is IAP E3 ubiquitin ligase binding moiety

thereby providing a compound of formula I-a-14:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, Ring T, L, X, L^(x), R^(x), R^(y), x, and y is asdefined above and described in embodiments herein, both singly and incombination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and LBM is IAP E3 ubiquitin ligasebinding moiety

thereby providing a compound of formula I-a-15:

or a pharmaceutically acceptable salt thereof, wherein each of Ring T,L, L^(x), X, R^(x), R^(y), x, and y is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and LBM is IAP E3 ubiquitin ligasebinding moiety

thereby providing a compound of formula I-a-16:

or a pharmaceutically acceptable salt thereof, wherein each of Ring T,L, L^(x), X, R^(x), R^(y), x, and y is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and LBM is IAP E3 ubiquitin ligasebinding moiety

thereby providing a compound of formula I-a-17:

or a pharmaceutically acceptable salt thereof, wherein each of Ring T,L, L^(x), X, R^(x), R^(y), x, and y is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and LBM is VHL E3 ubiquitin ligasebinding moiety

thereby providing a compound of formula I-a-18:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R²,R², Ring T, L, L^(x), X, R^(x), R^(y), x, and y is as defined above anddescribed in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and LBM is VHL E3 ubiquitin ligasebinding moiety

thereby providing a compound of formula I-a-19:

or a pharmaceutically acceptable salt thereof, wherein each of Ring T,L, L^(x), X, R^(x), R^(y), x, and y is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and LBM is VHL E3 ubiquitin ligasebinding moiety

thereby providing a compound of formula I-a-20:

or a pharmaceutically acceptable salt thereof, wherein each of Ring T,L, L^(x), X, R^(x), R^(y), x, and y is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and LBM is VHL E3 ubiquitin ligasebinding moiety

thereby providing a compound of formula I-a-21:

or a pharmaceutically acceptable salt thereof, wherein each of Ring T,L, L^(x), X, R^(x), R^(y), x, and y is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and LBM is VHL E3 ubiquitin ligasebinding moiety

thereby providing a compound of formula I-a-22:

or a pharmaceutically acceptable salt thereof, wherein each of Ring T,L, R¹, R³, Y, L^(x), X, R^(x), R^(y), x, and y is as defined above anddescribed in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and LBM is VHL E3 ubiquitin ligasebinding moiety

thereby providing a compound of formula I-a-23:

or a pharmaceutically acceptable salt thereof, wherein each of Ring T,L, L^(x), X, R^(x), R^(y), x, and y is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and LBM is VHL E3 ubiquitin ligasebinding moiety

thereby providing a compound of formula I-a-24:

or a pharmaceutically acceptable salt thereof, wherein each of Ring T,L, L^(x), X, R^(x), R^(y), x, and y is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and LBM is VHL E3 ubiquitin ligasebinding moiety

thereby providing a compound of formula I-a-25:

or a pharmaceutically acceptable salt thereof, wherein each of Ring T,L, L^(x), X, R^(x), R^(y), x, and y is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and LBM is VHL E3 ubiquitin ligasebinding moiety

thereby providing a compound of formula I-a-26:

or a pharmaceutically acceptable salt thereof, wherein the VHL bindingmoiety forms a macrocycle with L as shown and the IRAK binding moietyattaches to any modifiable carbon, oxygen, or nitrogen atom of L,wherein each of Ring T, L, L^(x), X, R^(x), R^(y), x, and y is asdefined above and described in embodiments herein, both singly and incombination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and LBM is VHL E3 ubiquitin ligasebinding moiety

thereby providing a compound of formula I-a-27:

or a pharmaceutically acceptable salt thereof, wherein the VHL bindingmoiety forms a macrocycle with L as shown and the IRAK binding moietyattaches to any modifiable carbon, oxygen, or nitrogen atom of L,wherein each of Ring T, L, L^(x), X, R^(x), R^(y), x, and y is asdefined above and described in embodiments herein, both singly and incombination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and LBM is VHL E3 ubiquitin ligasebinding moiety

thereby providing a compound of formula I-a-28:

or a pharmaceutically acceptable salt thereof, wherein each of Ring T,L, L^(x), X, R^(x), R^(y), x, and y is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and LBM is VHL E3 ubiquitin ligasebinding moiety

thereby providing a compound of formula I-a-29:

or a pharmaceutically acceptable salt thereof, wherein each of Ring T,L, L^(x), X, R^(x), R^(y), x, and y is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and LBM is VHL E3 ubiquitin ligasebinding moiety

thereby providing a compound of formula I-a-30:

or a pharmaceutically acceptable salt thereof, wherein each of Ring T,L, L^(x), X, R^(x), R^(y), x, and y is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and LBM is VHL E3 ubiquitin ligasebinding moiety

thereby providing a compound of formula I-a-31:

or a pharmaceutically acceptable salt thereof, wherein each of Ring T,L, L^(x), X, R^(x), R^(y), x, and y is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and LBM is MDM2 E3 ubiquitin ligasebinding moiety

thereby providing a compound of formula I-a-32:

or a pharmaceutically acceptable salt thereof, wherein each of Ring T,R¹, R¹, R², R¹¹, R¹⁴, R¹⁵, L, L^(x), X, R^(x), R^(y), x, and y is asdefined above and described in embodiments herein, both singly and incombination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and LBM is MDM2 E3 ubiquitin ligasebinding moiety

thereby providing a compound of formula I-a-33:

or a pharmaceutically acceptable salt thereof, wherein each of Ring T,L, L^(x), X, R^(x), R^(y), x, and y is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and LBM is MDM2 E3 ubiquitin ligasebinding moiety

thereby providing a compound of formula I-a-34:

or a pharmaceutically acceptable salt thereof, wherein each of Ring T,L, L^(x), X, R^(x), R^(y), x, and y is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and LBM is MDM2 E3 ubiquitin ligasebinding moiety

thereby providing a compound of formula I-a-35:

or a pharmaceutically acceptable salt thereof, wherein each of Ring T,L, L^(x), X, R^(x), R^(y), m, x, and y is as defined above and describedin embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and LBM is MDM2 E3 ubiquitin ligasebinding moiety

thereby providing a compound of formula I-a-36:

or a pharmaceutically acceptable salt thereof, wherein each of Ring T,L, L^(x), X, R^(x), R^(y), m, x, and y is as defined above and describedin embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and LBM is MDM2 E3 ubiquitin ligasebinding moiety

thereby providing a compound of formula I-a-37:

or a pharmaceutically acceptable salt thereof, wherein each of Ring T,L, L^(x), X, R^(x), R^(y), m, x, and y is as defined above and describedin embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and LBM is MDM2 E3 ubiquitin ligasebinding moiety

thereby providing a compound of formula I-a-38:

or a pharmaceutically acceptable salt thereof, wherein each of Ring T,L, L^(x), X, R^(x), R^(y), m, x, and y is as defined above and describedin embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and LBM is DCAF16 E3 ubiquitinligase binding moiety

as shown, to provide a compound of formula I-a-39:

or a pharmaceutically acceptable salt thereof, wherein each of Ring T,L, L^(x), X, R^(x), R^(y), m, x, and y is as defined above and describedin embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and LBM is RNF4 E3 ubiquitin ligasebinding moiety

thereby providing a compound of formula I-a-40:

or a pharmaceutically acceptable salt thereof, wherein each of Ring T,L, L^(x), X, R^(x), R^(y), m, x, and y is as defined above and describedin embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and LBM is RNF114 E3 ubiquitinligase binding moiety

thereby providing a compound of formula I-a-41:

or a pharmaceutically acceptable salt thereof, wherein each of Ring T,L, L^(x), X, R^(x), R^(y), m, x, and y is as defined above and describedin embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and LBM is KLHDC2 E3 ubiquitinligase binding moiety

wherein R* is methyl or hydrogen, thereby providing a compound offormula I-a-42a or I-a-42b:

or a pharmaceutically acceptable salt thereof, wherein each of Ring T,L, L^(x), X, R^(x), R^(y), m, x, and y is as defined above and describedin embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-a, wherein Ring Q is benzo and LBM is AHR E3 ubiquitin ligasebinding moiety

thereby providing a compound of formula I-a-43:

or a pharmaceutically acceptable salt thereof, wherein each of Ring T,L, L^(x), X, R^(x), R^(y), m, x, and y is as defined above and describedin embodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula I, wherein Ring Q is benzo and LBM is a CRBN E3 ubiquitin ligasebinding moiety thereby forming a compound of formula I-qqq:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, wherein:

-   each X¹ is independently —CH₂—, —O—, —NR—, —CF₂—,

—C(O)—, —C(S)—, or

-   X² and X³ are independently —CH₂—, —C(O)—, —C(S)—, or

-   Z¹ and Z² are independently a carbon atom or a nitrogen atom;-   Ring A is a fused ring selected from benzo, a 4-6 membered saturated    or partially unsaturated carbocyclic or heterocyclic ring having 1-3    heteroatoms independently selected from nitrogen, oxygen, and    sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur;-   L¹ is a covalent bond or a C₁₋₃ bivalent straight or branched    saturated or unsaturated hydrocarbon chain wherein 1-2 methylene    units of the chain are independently and optionally replaced with    —O—, —S—, —C(O)—, —C(S)—, —CR₂—, —CRF—, —CF₂—, —NR—, or —S(O)₂—;-   each R¹ is independently selected from hydrogen, deuterium, R⁴,    halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R,    —CF₂R, —CR₂F, —CF₃, —CR₂(OR), —CR₂(NR₂), —C(O)R, —C(O)OR, —C(O)NR₂,    —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —C(S)NR₂, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)NR₂, —N(R)S(O)₂R, —OP(O)R₂, —OP(O)(OR)₂, —OP(O)(OR)NR₂,    —OP(O)(NR₂)₂, —Si(OR)R₂, and —SiR₃; or    -   two R¹ groups are optionally taken together to form an        optionally substituted 5-8 membered partially unsaturated or        aryl fused ring having 0-2 heteroatoms independently selected        from nitrogen, oxygen, or sulfur;-   each R is independently selected from hydrogen, or an optionally    substituted group selected from C₁₋₆ aliphatic, phenyl, a 4-7    membered saturated or partially unsaturated heterocyclic having 1-2    heteroatoms independently selected from nitrogen, oxygen, and    sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same carbon or nitrogen are optionally taken        together with their intervening atoms to form an optionally        substituted 4-7 membered saturated, partially unsaturated, or        heteroaryl ring having 0-3 heteroatoms, in addition to the        carbon or nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   R² is selected from

or hydrogen;

-   Ring B is phenyl, a 4-10 membered saturated or partially unsaturated    mono- or bicyclic carbocyclic or heterocyclic ring having 1-3    heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, wherein    Ring B is further optionally substituted with 1-2 oxo groups;-   each R³ is independently selected from hydrogen, deuterium, R⁴,    halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R,    —CF₂R, —CF₃, —CR₂(OR), —CR₂(NR₂), —C(O)R, —C(O)OR, —C(O)NR₂,    —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)NR₂, —N(R)S(O)₂R, —OP(O)R₂, —OP(O)(OR)₂, —OP(O)(OR)NR₂,    —OP(O)(NR₂)₂, and —SiR₃;-   each R⁴ is independently selected from an optionally substituted    group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated    or partially unsaturated heterocyclic ring having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur;-   is a single or double bond;-   m is 0, 1, 2, 3 or 4;-   n is 0, 1, 2, 3 or 4; and-   o is 0, 1, or 2.

As defined above and described herein each X¹ is independently acovalent bond, —CH₂—, —O—, —NR—, —CF₂—,

—C(O)—, —C(S)—, or

In some embodiments, X¹ is a covalent bond. In some embodiments, X¹ is—CH₂—. In some embodiments, X¹ is —O—. In some embodiments, X¹ is —NR—.In some embodiments, X¹ is —CF₂—. In some embodiments, X¹ is

In some embodiments, X¹ is —C(O)—. In some embodiments, X¹ is —C(S)—. Insome embodiments, X¹ is

In certain embodiments, X¹ is selected from those shown in the compoundsof Table 1.

As defined above and described herein, X² and X³ are independently—CH₂—, —C(O)—, —C(S)—, or

In some embodiments, X² and X³ are independently —CH₂—. In someembodiments, X² and X³ are independently —C(O)—. In some embodiments, X²and X³ are independently —C(S)—. In some embodiments, X² and X³ areindependently

In certain embodiments, X² and X³ are independently selected from thoseshown in the compounds of Table 1.

As define above and described herein, Z¹ and Z² are independently acarbon atom or a nitrogen atom.

In some embodiments, Z¹ and Z² are independently a carbon atom. In someembodiments, Z¹ and Z² are independently a carbon atom.

In certain embodiments, Z¹ and Z² are independently selected from thoseshown in the compounds of Table 1.

As defined above and described herein, Ring A is fused ring selectedfrom benzo or a 5-6 membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur.

In some embodiments, Ring A is benzo. In some embodiments, Ring A is a5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur.

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In certain embodiments, Ring A is selected from those shown in thecompounds of Table 1.

As defined above and described herein, L¹ is a covalent bond or a C₁₋₃bivalent straight or branched saturated or unsaturated hydrocarbon chainwherein 1-2 methylene units of the chain are independently andoptionally replaced with —O—, —S—, —C(O)—, —C(S)—, —CR₂—, —CRF—, —CF₂—,—NR—, or —S(O)₂—.

In some embodiments, L¹ is a covalent bond. In some embodiments, L¹ is aC₁₋₃ bivalent straight or branched saturated or unsaturated hydrocarbonchain wherein 1-2 methylene units of the chain are independently andoptionally replaced with —O—, —S—, —C(O)—, —C(S)—, —CR₂—, —CRF—, —CF₂—,—NR—, or —S(O)₂—.

In some embodiments, L¹ is —C(O)—.

In certain embodiments, L¹ is selected from those shown in the compoundsof Table 1.

As defined above and described herein, each R¹ is independently selectedfrom hydrogen, deuterium, R⁴, halogen, —CN, —NO₂, —OR, —SR, —NR₂,—S(O)₂R, —S(O)₂NR₂—S(O)R. —CF₂R, —CF₃, —CR₂(OR), —CR₂(NR₂), —C(O)R,—C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —C(S)NR₂,—N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, —N(R)S(O)₂R, —OP(O)R₂,—OP(O)(OR)₂, —OP(O)(OR)NR₂, —OP(O)(NR₂)₂, —Si(OR)R₂, and —SiR₃, or twoR¹ groups are optionally taken together to form an optionallysubstituted 5-8 membered partially unsaturated or aryl fused ring having0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R¹ is hydrogen. In some embodiments, R¹ isdeuterium. In some embodiments, R¹ is R⁴. In some embodiments, R¹ ishalogen. In some embodiments, R¹ is —CN. In some embodiments, R¹ is—NO₂. In some embodiments, R¹ is —OR. In some embodiments, R¹ is —SR. Insome embodiments, R¹ is —NR₂. In some embodiments, R¹ is —S(O)₂R. Insome embodiments, R¹ is —S(O)₂NR₂. In some embodiments, R¹ is —S(O)R. Insome embodiments, R¹ is —CF₂R. In some embodiments, R¹ is —CF₃. In someembodiments, R¹ is —CR₂(OR). In some embodiments, R¹ is —CR₂(NR₂). Insome embodiments, R¹ is —C(O)R. In some embodiments, R¹ is —C(O)OR. Insome embodiments, R¹ is —C(O)NR₂. In some embodiments, R¹ is—C(O)N(R)OR. In some embodiments, R¹ is —OC(O)R. In some embodiments, R¹is —OC(O)NR₂. In some embodiments, R¹ is —C(S)NR₂. In some embodiments,R¹ is —N(R)C(O)OR. In some embodiments, R¹ is —N(R)C(O)R. In someembodiments, R¹ is —N(R)C(O)NR₂. In some embodiments, R¹ is —N(R)S(O)₂R.In some embodiments, R¹ is —OP(O)R₂. In some embodiments, R¹ is—OP(O)(OR)₂. In some embodiments, R¹ is —OP(O)(OR)NR₂. In someembodiments, R¹ is —OP(O)(NR₂)₂. In some embodiments, R¹ is —Si(OR)R₂.In some embodiments, R¹ is —SiR₃, In some embodiments, two R¹ groups areoptionally taken together to form an optionally substituted 5-8 memberedpartially unsaturated or aryl fused ring having 0-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R¹ is fluoro. In some embodiments, R¹ is bromo. Insome embodiments, R¹ is methyl. In some embodiments, R¹ is —OH. In someembodiments, R¹ is —NH₂. In some embodiments, R¹ is —NHCH₃. In someembodiments, R¹ is —N(CH₃)₂. In some embodiments, R¹ is —NHCH(CH₃)₂. Insome embodiments, R¹ is —NHSO₂CH₃. In some embodiments, R¹ is —CH₂OH. Insome embodiments, R¹ is —CH₂NH₂. In some embodiments, R¹ is —C(O)NH₂. Insome embodiments, R¹ is —C(O)NHCH₃. In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In certain embodiments, each R¹ is independently selected from thoseshown in the compounds of Table 1.

As defined above and described here, each R is independently selectedfrom hydrogen, or an optionally substituted group selected from C₁₋₆aliphatic, phenyl, a 4-7 membered saturated or partially unsaturatedheterocyclic having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur, or two R groups on the same carbon or nitrogen are optionallytaken together with their intervening atoms to form an optionallysubstituted 4-7 membered saturated, partially unsaturated, or heteroarylring having 0-3 heteroatoms, in addition to the carbon or nitrogen,independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R is hydrogen. In some embodiments, R is anoptionally substituted (% 6 aliphatic. In some embodiments, R is anoptionally substituted phenyl. In some embodiments, R is an optionallysubstituted 4-7 membered saturated or partially unsaturated heterocyclichaving 1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In some embodiments, R is an optionally substituted a 5-6membered heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur. In some embodiments, two R groups onthe same carbon or nitrogen are optionally taken together with theirintervening atoms to form an optionally substituted 4-7 memberedsaturated, partially unsaturated, or heteroaryl ring having 0-3heteroatoms, in addition to the carbon or nitrogen, independentlyselected from nitrogen, oxygen, and sulfur.

As defined above and described herein, R² is selected from

or hydrogen.

In some embodiment R² is

In some embodiments, R² is hydrogen.

In certain embodiments, R² is selected from those shown in the compoundsof Table 1.

As defined above and described herein, Ring B is phenyl, a 4-10 memberedsaturated or partially unsaturated mono- or bicyclic carbocyclic orheterocyclic ring having 1-3 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur, wherein Ring B is further optionally substituted with 1-2 oxogroups.

In some embodiments, Ring B is phenyl. In some embodiments, Ring B is a4-10 membered saturated or partially unsaturated mono- or bicycliccarbocyclic or heterocyclic ring having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur In some embodiments, Ring Bis a 5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Bis further optionally substituted with 1-2 oxo groups.

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments Ring B is

In some embodiments Ring B is

In some embodiments Ring B is

In some embodiments Ring B is

In In some embodiments Ring B is

In some embodiments Ring B is

In some embodiments Ring B is

In some embodiments Ring B is

In some embodiments Ring B is

In some embodiments Ring B is

In some embodiments Ring B is

In certain embodiments, Ring B is selected from those shown in thecompounds of Table 1.

As defined above and described herein, each R³ is independently selectedfrom hydrogen, deuterium, R⁴, halogen, —CN, —NO₂, —OR, —SR, —NR₂,—S(O)₂R, —S(O)₂NR₂—S(O)R. —CF₂R, —CF₃, —CR₂(OR), —CR₂(NR₂), —C(O)R,—C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,—N(R)C(O)R, —N(R)C(O)NR₂, —N(R)S(O)₂R, —OP(O)R₂, —OP(O)(OR)₂,—OP(O)(OR)NR₂, —OP(O)(NR₂)₂, and —SiR₃

In some embodiments, R³ is hydrogen. In some embodiments, R³ isdeuterium. In some embodiments, R³ is R⁴. In some embodiments, R³ ishalogen. In some embodiments, R³ is —CN. In some embodiments, R³ is—NO₂. In some embodiments, R³ is —OR. In some embodiments, R³ is —SR. Insome embodiments, R³ is —NR₂. In some embodiments, R³ is —S(O)₂R. Insome embodiments, R³ is —S(O)₂NR₂. In some embodiments, R³ is —S(O)R. Insome embodiments, R³ is —CF₂R. In some embodiments, R³ is —CF₃. In someembodiments, R³ is —CR₂(OR). In some embodiments, R³ is —CR₂(NR₂). Insome embodiments, R³ is —C(O)R. In some embodiments, R³ is —C(O)OR. Insome embodiments, R³ is —C(O)NR₂. In some embodiments, R³ is—C(O)N(R)OR. In some embodiments, R³ is —OC(O)R. In some embodiments, R³is —OC(O)NR₂. In some embodiments, R³ is —N(R)C(O)OR. In someembodiments, R³ is —N(R)C(O)R. In some embodiments, R³ is —N(R)C(O)NR₂.In some embodiments, R³ is —N(R)S(O)₂R. In some embodiments, R³ is—OP(O)R₂. In some embodiments, R³ is —OP(O)(OR)₂. In some embodiments,R³ is —OP(O)(OR)NR₂. In some embodiments, R³ is —OP(O)(NR₂)₂. In someembodiments, R³ is —SiR₃.

In certain embodiments, R³ is selected from those shown in the compoundsof Table 1.

As defined above and described herein, each R⁴ is independently anoptionally substituted group selected from C₁₋₆ aliphatic, phenyl, a 4-7membered saturated or partially unsaturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur,and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur.

In some embodiments, R⁴ is an optionally substituted C₁₋₆ aliphatic. Insome embodiments, R⁴ is an optionally substituted phenyl. In someembodiments, R⁴ is an optionally substituted 4-7 membered saturated orpartially unsaturated heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, R⁴ is an optionally substituted 5-6 membered heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur.

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In certain embodiments, R⁴ is selected from those shown in the compoundsof Table 1.

As defined above and described herein,

is a single or double bond.

In some embodiments,

is a single bond. In some embodiments, is a double bond.

In certain embodiments,

is selected from those shown in the compounds of Table 1.

As defined above and described herein, m is 0, 1, 2, 3 or 4.

In some embodiments, m is 0. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 3. In some embodiments, mis 4.

In certain embodiments, m is selected from those shown in the compoundsof Table 1.

As defined above and described herein, n is 0, 1, 2, 3 or 4.

In some embodiments, n is 0. In some embodiments, n is 1. In someembodiments, n is 2. In some embodiments, n is 3. In some embodiments, nis 4.

In certain embodiments, n is selected from those shown in the compoundsof Table 1.

As defined above and described herein, o is 0, 1, or 2.

In some embodiments, n is 0. In some embodiments, n is 1. In someembodiments, m is 2.

In certain embodiments, o is selected from those shown in the compoundsof Table 1.

In some embodiments, the present invention provides a compound offormula I-qqq, wherein Ring A is benzo, o is 1, X¹ is —CH₂—, X² and X³are —C(O)—, and Z¹ and Z² are carbon atoms as shown, to provide acompound of formula I-qqq-1:

or a pharmaceutically acceptable salt thereof, wherein each of IRAK, L,L¹, R¹, R², and m is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-qqq, wherein Ring A is imidazolyl, o is 1, X¹ is —CH₂—, X² andX³ are —C(O)—, and Z¹ and Z² are carbon atoms as shown, to provide acompound of formula I-qqq-2:

or a pharmaceutically acceptable salt thereof, wherein each of IRAK, L,L¹, and R² is as defined above and described in embodiments herein, bothsingly and in combination.

In some embodiments, the present invention provides a compound offormula I-qqq, wherein Ring A is imidazolyl, o is 1, X¹ is —CH₂—, X² andX³ are —C(O)—, and Z¹ and Z² are carbon atoms as shown, to provide acompound of formula I-qqq-3:

or a pharmaceutically acceptable salt thereof, wherein each of IRAK, L,L¹, and R² is as defined above and described in embodiments herein, bothsingly and in combination.

In some embodiments, the present invention provides a compound offormula I-qqq, wherein Ring A is oxazolyl, o is 1, X¹ is —CH₂—, X² andX³ are —C(O)—, and Z¹ and Z² are carbon atoms as shown, to provide acompound of formula I-qqq-4:

or a pharmaceutically acceptable salt thereof, wherein each of IRAK andL is as defined above and described in embodiments herein, both singlyand in combination.

In some embodiments, the present invention provides a compound offormula I-qqq, wherein Ring A is benzo, o is 0, X¹ is a covalent bond,X² and X³ are —C(O)—, and Z¹ and Z² are carbon atoms as shown, toprovide a compound of formula I-qqq-5:

or a pharmaceutically acceptable salt thereof, wherein each of IRAK, L,L¹, R¹, R², and m is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-qqq, wherein Ring A is benzo, o is 1, X¹ is —O—, X² and X³ are—C(O)—, and Z¹ and Z² are carbon atoms as shown, to provide a compoundof formula I-qqq-6:

or a pharmaceutically acceptable salt thereof, wherein each of IRAK, L,L¹, R¹, R², and m is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-qqq, wherein Ring A is benzo, o is 1, X¹ is —NR—, X² and X³are —C(O)—, and Z¹ and Z² are carbon atoms as shown, to provide acompound of formula I-qqq-7:

or a pharmaceutically acceptable salt thereof, wherein each of IRAK, L,L¹, R, R¹, R², and m is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-qqq, wherein Ring A is benzo, o is 1, X¹ is —CF₂—, X² and X³are —C(O)—, and Z¹ and Z² are carbon atoms as shown, to provide acompound of formula I-qqq-8:

or a pharmaceutically acceptable salt thereof, wherein each of IRAK, L,L¹, R¹, R², and m is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-qqq, wherein Ring A is benzo, o is 1, X¹ is

X² and X³ are —C(O)—, and Z¹ and Z² are carbon atoms as shown, toprovide a compound of formula I-qqq-9:

or a pharmaceutically acceptable salt thereof, wherein each of IRAK, L,L¹, R¹, R², and m is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-qqq, wherein Ring A is pyridyl, o is 1, X¹ is —CH₂—, X² and X³are —C(O)—, and Z¹ and Z² are carbon atoms as shown, to provide acompound of formula I-qqq-10:

or a pharmaceutically acceptable salt thereof, wherein each of IRAK, L,L¹, R¹, R², and m is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-qqq, wherein Ring A is pyridyl, o is 1, X¹ is —CH₂—, X² and X³are —C(O)—, and Z¹ and Z² are carbon atoms as shown, to provide acompound of formula I-qqq-11:

or a pharmaceutically acceptable salt thereof, wherein each of IRAK, L,L¹, R¹, R², and m is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-qqq, wherein Ring A is benzo, o is 1, X¹, X² and X³ are—C(O)—, and Z¹ and Z² are carbon atoms as shown, to provide a compoundof formula I-qqq-12:

or a pharmaceutically acceptable salt thereof, wherein each of IRAK, L,L¹, R¹, R², and m is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is selected from those in Table 1, below.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a RPN13 binding moiety thereby forming acompound of formula I-rrr:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein each ofthe variables A, Y, and Z is as described and defined in WO 2019/165229,the entirety of each of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a Ubr1 binding moiety as described inShanmugasundaram, K. et al, J. Bio. Chem. 2019, doi:10.1074/jbc.AC119.010790, the entirety of each of which is hereinincorporated by reference, thereby forming a compound of formula I-sss-1or I-sss-2:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a CRBN E3 ubiquitin ligase binding moietythereby forming a compound of formula I-ttt-1,1-ttt-2,1-ttt-3 orI-ttt-4:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein each ofthe variables Y, A¹, and A³ is as described and defined in WO2019/236483, the entirety of each of which is herein incorporated byreference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is human kelch-like ECH-associated protein 1(KEAP1) thereby forming a compound of formula I-uuu:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, both singly and incombination.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is KEAP1 binding moiety as recited in Lu et al.,Euro. J. Med. Chem., 2018, 146:251-9, thereby forming a compound offormula I-vw:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, both singly and incombination.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is KEAP1-NRF2 binding moiety thereby forming acompound of formula I-www-1 or I-www-2:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein each ofthe variables R, R₁, R₅, and R₈ is as described and defined in WO2020/018788, the entirety of each of which is herein incorporated byreference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is KEAP1-NRF2 binding moiety as recited in Tonget al., “Targeted Protein Degradation via a Covalent Reversible DegraderBased on Bardoxolone”, ChemRxiv 2020, thereby forming a compound offormula I-xxx-1 or T-xxx-2:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, both singly and incombination.

In certain embodiments, the present invention provides a compound offormula I:

-   or a pharmaceutically acceptable salt thereof, wherein L and IRAK    are as defined above and described in embodiments herein, wherein:-   X¹ and X² are independently a covalent bond, —CR₂—, —O—, —CF₂—,

or

-   -   X¹ and X² are —CR═CR—;

-   X³ and X⁴ are independently —CH₂—, —C(O)—, —C(S)—, or

-   Ring X and Ring Y are independently fused rings selected from a 5-6    membered saturated, partially unsaturated, or heteroaryl ring having    0-4 heteroatoms, in addition to the nitrogen already depicted in    Ring X and Ring Y, independently selected from nitrogen, oxygen, and    sulfur;-   each R^(a) and R^(b) are independently selected from hydrogen,    deuterium, R^(c), halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R,    —S(O)₂NR₂, —S(O)R, —CF₂R, —CF₃, —CR₂(OR), —CR₂(NR₂), —C(O)R,    —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —C(S)NR₂,    N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, —N(R)S(O)₂R, —OP(O)R₂,    —OP(O)(OR)₂, —OP(O)(OR)NR₂, —OP(O)(NR₂)₂, —Si(OR)R₂, and —SiR₃;-   each R is independently selected from hydrogen, or an optionally    substituted group selected from C₁₋₆ aliphatic, phenyl, a 4-7    membered saturated or partially unsaturated heterocyclic having 1-2    heteroatoms independently selected from nitrogen, oxygen, and    sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same carbon or nitrogen are optionally taken        together with their intervening atoms to form an optionally        substituted 4-7 membered saturated, partially unsaturated, or        heteroaryl ring having 0-3 heteroatoms, in addition to the        carbon or nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   each R^(c) is independently selected from an optionally substituted    group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated    or partially unsaturated heterocyclic ring having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur;-   a is 0, 1, 2, 3 or 4; and-   b is 0, 1, 2, 3 or 4;

As defined above and described herein, X¹ and X² are independently acovalent bond, —CR₂—, —O—, —CF₂—,

or X¹ and X² are —CR═CR—.

In some embodiments, X¹ is a covalent bond. In some embodiments, X¹ is—CR₂—. In some embodiments, X¹ is —CH₂—. In some embodiments, X¹ is —O—.In some embodiments, X¹ is —CF₂—. In some embodiments, X¹ is

In some embodiments, X² is a covalent bond. In some embodiments, X² is—CR₂—. In some embodiments, X² is —CH₂—. In some embodiments, X² is —O—.In some embodiments, X² is —CF₂—. In some embodiments, X² is

In some embodiments, X¹ and X² are —CR═CR—. In some embodiments, X¹ andX² are —CH═CH—.

In some embodiments, X¹ and X² are independently selected from thoseshown in the compounds of Table 1.

As defined above and described herein, X³ and X⁴ are independently—CH₂—, —C(O)—, —C(S)—, or

In some embodiments, X³ is —CH₂—. In some embodiments, X³ is —C(O)—. Insome embodiments, X³ is —C(S)—. In some embodiments, X³ is

In some embodiments, X⁴ is —CH₂—. In some embodiments, X⁴ is —C(O)—. Insome embodiments, X⁴ is —C(S)—. In some embodiments, X⁴ is

In some embodiments, X³ and X⁴ are selected from those shown in thecompounds of Table 1.

As defined above and described herein, Ring X and Ring Y areindependently fused rings selected from a 5-6 membered saturated,partially unsaturated, or heteroaryl ring having 0-4 heteroatoms, inaddition to the nitrogen already depicted in Ring X and Ring Y,independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, Ring X and Ring Y are independently fused ringsselected from a 5-6 membered saturated, partially unsaturated, orheteroaryl ring having 0-4 heteroatoms, in addition to the nitrogenalready depicted in Ring X and Ring Y, independently selected fromnitrogen, oxygen, and sulfur.

In some embodiments, Ring X is

In some embodiments, Ring X is

In some embodiments, Ring X is

In some embodiments, Ring X is

In some embodiments, Ring X is

In some embodiments, Ring X is

In some embodiments, Ring X is

In some embodiments, Ring X is

In some embodiments, Ring X is

In some embodiments, Ring X is

In some embodiments, Ring X is

In some embodiments, Ring X is

In some embodiments, Ring X is

In some embodiments, Ring X is

In some embodiments, Ring X is

In some embodiments, Ring X is

In certain embodiments, Ring X and Ring Y are selected from those shownin the compounds of Table 1.

As defined above and described herein, each R^(a) and R^(b) areindependently selected from hydrogen, deuterium, R^(c), halogen, —CN,—NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂. —S(O)R, —CFR₂, —CF₂R, —CF₃,—CR₂(OR), —CR₂(NR₂), —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R,—OC(O)NR₂, —C(S)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, —N(R)S(O)₂R,—OP(O)R₂, —OP(O)(OR)₂, —OP(O)(OR)NR₂, —OP(O)(NR₂)₂, —Si(OR)R₂, and—SiR₃.

In some embodiments, R^(a) is hydrogen. In some embodiments, R^(a) isdeuterium. In some embodiments, R^(a) is R^(c). In some embodiments,R^(a) is halogen. In some embodiments, R^(a) is —CN. In someembodiments, R^(a) is —NO₂. In some embodiments, R^(a) is —OR. In someembodiments, R^(a) is —SR. In some embodiments, R^(a) is —NR₂. In someembodiments, R^(a) is —S(O)₂R. In some embodiments, R^(a) is —S(O)₂NR₂.In some embodiments, R^(a) is —S(O)R. In some embodiments, R^(a) is—CFR₂. In some embodiments, R^(a) is —CF₂R. In some embodiments, R^(a)is —CF₃. In some embodiments, R^(a) is —CR₂(OR). In some embodiments,R^(a) is —CR₂(NR₂). In some embodiments, R^(a) is —C(O)R. In someembodiments, R^(a) is —C(O)OR. In some embodiments, R^(a) is —C(O)NR₂.In some embodiments, R^(a) is —C(O)N(R)OR. In some embodiments, R^(a) is—OC(O)R. In some embodiments, R^(a) is —OC(O)NR₂. In some embodiments,R^(a) is —C(S)NR₂. In some embodiments, R^(a) is —N(R)C(O)OR. In someembodiments, R^(a) is —N(R)C(O)R. In some embodiments, R^(a) is—N(R)C(O)NR₂. In some embodiments, R^(a) is —N(R)S(O)₂R. In someembodiments, R^(a) is —OP(O)R₂. In some embodiments, R^(a) is—OP(O)(OR)₂. In some embodiments, R^(a) is —OP(O)(OR)NR₂. In someembodiments, R^(a) is —OP(O)(NR₂)₂. In some embodiments, R^(a) is—Si(OR)R₂. In some embodiments, R^(a) is —SiR₃.

In some embodiments, R^(b) is hydrogen. In some embodiments, R^(b) isdeuterium. In some embodiments, R^(b) is R^(c). In some embodiments,R^(b) is halogen. In some embodiments, R^(b) is —CN. In someembodiments, R^(b) is —NO₂. In some embodiments, R^(b) is —OR. In someembodiments, R^(b) is —SR. In some embodiments, R^(b) is —NR₂. In someembodiments, R^(b) is —S(O)₂R. In some embodiments, R^(b) is —S(O)₂NR₂.In some embodiments, R^(b) is —S(O)R. In some embodiments, R^(b) is—CFR₂. In some embodiments, R^(b) is —CF₂R. In some embodiments, R^(b)is —CF₃. In some embodiments, R^(b) is —CR₂(OR). In some embodiments,R^(b) is —CR₂(NR₂). In some embodiments, R^(b) is —C(O)R. In someembodiments, R^(b) is —C(O)OR. In some embodiments, R^(b) is —C(O)NR₂.In some embodiments, R^(b) is —C(O)N(R)OR. In some embodiments, R^(b) is—OC(O)R. In some embodiments, R^(b) is —OC(O)NR₂. In some embodiments,R^(b) is —C(S)NR₂. In some embodiments, R^(b) is —N(R)C(O)OR. In someembodiments, R^(b) is —N(R)C(O)R. In some embodiments, R^(b) is—N(R)C(O)NR₂. In some embodiments, R^(b) is —N(R)S(O)₂R. In someembodiments, R^(b) is —OP(O)R₂. In some embodiments, R^(b) is—OP(O)(OR)₂. In some embodiments, R^(b) is —OP(O)(OR)NR₂. In someembodiments, R^(b) is —OP(O)(NR₂)₂. In some embodiments, R^(b) is—Si(OR)R₂. In some embodiments, R^(b) is —SiR₃.

In certain embodiments, each R^(a) and R^(b) are selected from thoseshown in the compounds of Table 1.

As defined above and described herein, each R is independently selectedfrom hydrogen, or an optionally substituted group selected from C₁₋₆aliphatic, phenyl, a 4-7 membered saturated or partially unsaturatedheterocyclic having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur, or two R groups on the same carbon or nitrogen are optionallytaken together with their intervening atoms to form an optionallysubstituted 4-7 membered saturated, partially unsaturated, or heteroarylring having 0-3 heteroatoms, in addition to the carbon or nitrogen,independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R is hydrogen. In some embodiments, R is anoptionally substituted (% 6 aliphatic. In some embodiments, R is anoptionally substituted phenyl. In some embodiments, R is an optionallysubstituted 4-7 membered saturated or partially unsaturated heterocyclichaving 1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In some embodiments, R is an optionally substituted a 5-6membered heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur. In some embodiments, two R groups onthe same carbon or nitrogen are optionally taken together with theirintervening atoms to form an optionally substituted 4-7 memberedsaturated, partially unsaturated, or heteroaryl ring having 0-3heteroatoms, in addition to the carbon or nitrogen, independentlyselected from nitrogen, oxygen, and sulfur.

In certain embodiments, R is selected from those shown in the compoundsof Table 1.

As defined above and described herein, each R^(c) is independently anoptionally substituted group selected from C₁₋₆ aliphatic, phenyl, a 4-7membered saturated or partially unsaturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur,and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur.

In some embodiments, R^(c) is an optionally substituted C₁₋₆ aliphatic.In some embodiments, R^(c) is an optionally substituted phenyl. In someembodiments, R^(c) is an optionally substituted 4-7 membered saturatedor partially unsaturated heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, R^(c) is an optionally substituted 5-6 membered heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur.

In certain embodiments, R^(c) is selected from those shown in thecompounds of Table 1.

As defined above and described herein, a is 0, 1, 2, 3 or 4.

In some embodiments, a is 0. In some embodiments, a is 1. In someembodiments, a is 2. In some embodiments, a is 3. In some embodiments, ais 4.

In certain embodiments, a is selected from those shown in the compoundsof Table 1.

As defined above and described herein, b is 0, 1, 2, 3 or 4.

In some embodiments, b is 0. In some embodiments, b is 1. In someembodiments, b is 2. In some embodiments, b is 3. In some embodiments, bis 4.

In certain embodiments, b is selected from those shown in the compoundsof Table 1.

In some embodiments, the present invention provides a compound offormula I-yyy, wherein X¹ and X² are —CH₂—, and X³ and X⁴ are —C(O)— asshown, to provide a compound of formula I-yyy-1:

or a pharmaceutically acceptable salt thereof, wherein each of IRAK, L,Ring X, Ring Y, R^(a), R^(b), a, and b is as defined above and describedin embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-yyy, wherein X¹ and X² are —CH₂—, X³ and X⁴ are —C(O)—, andRing Y is

as shown, to provide a compound of formula I-yyy-2:

or a pharmaceutically acceptable salt thereof, wherein each of IRAK, L,Ring X, R^(a), R^(b), a, and b is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-yyy, wherein X¹ and X² are —CH₂—, X³ and X⁴ are —C(O)—, andRing X is

as shown, to provide a compound of formula I-yyy-3:

or a pharmaceutically acceptable salt thereof, wherein each of IRAK, L,Ring Y, R^(a), R^(b), a, and b is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-yyy, wherein X¹ and X² are —CH₂—, X³ and X⁴ are —C(O)—, Ring Xis

and Ring Y is

as shown, to provide a compound of formula I-yyy-4:

or a pharmaceutically acceptable salt thereof, wherein each of IRAK, L,R^(a), R^(b), x, and y is as defined above and described in embodimentsherein, both singly and in combination.

Lysine Mimetic

In some embodiments, DIM is LBM as described above and herein. In someembodiments, DIM is lysine mimetic. In some embodiments, the covalentattachment of ubiquitin to a member of the IRAK kinase family (i.e.,IRAK-1, -2, -3, or -4) is achieved through the action of a lysinemimetic. In some embodiments, upon the binding of a compound of formulaI to IRAK-1, the moiety that mimics a lysine undergoes ubiquitinationthereby marking IRAK-1 for degradation via the Ubiquitin-ProteasomePathway (UPP). In some embodiments, upon the binding of a compound offormula I to IRAK-2, the moiety that mimics a lysine undergoesubiquitination thereby marking IRAK-2 for degradation via theUbiquitin-Proteasome Pathway (UPP). In some embodiments, upon thebinding of a compound of formula I to IRAK-3, the moiety that mimics alysine undergoes ubiquitination thereby marking IRAK-3 for degradationvia the Ubiquitin-Proteasome Pathway (UPP). In some embodiments, uponthe binding of a compound of formula I to IRAK-4, the moiety that mimicsa lysine undergoes ubiquitination thereby marking IRAK-4 for degradationvia the Ubiquitin-Proteasome Pathway (UPP).

In some embodiments, DIM is

In some embodiments, DIM is

In some embodiments, DIM is

In some embodiments, DIM is selected from those depicted in Table 1,below.

In some embodiments, the present invention provides the compound offormula I wherein DIM is

thereby forming a compound of formula I-kkk-1:

or a pharmaceutically acceptable salt thereof, wherein each of IRAK andU is as defined above and described in embodiments herein, both singlyand in combination.

In some embodiments, the present invention provides the compound offormula I wherein DIM is

thereby forming a compound of formula I-kkk-2:

or a pharmaceutically acceptable salt thereof, wherein each of IRAK andL is as defined above and described in embodiments herein, both singlyand in combination.

In some embodiments, the present invention provides the compound offormula I wherein DIM is

thereby forming a compound of formula I-kkk-3:

or a pharmaceutically acceptable salt thereof, wherein each of IRAK andL is as defined above and described in embodiments herein, both singlyand in combination.

In certain embodiments, the present invention provides a compound ofFormula I, wherein DIM is lysine mimetic

thereby forming a compound of formulae I-lll-1, I-lll-2, or I-lll-3,respectively:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein each ofthe variables R¹, R⁴, R⁵, A, B, E, Y, Y′, Z, Z′, and k are as definedand described in U.S. Pat. No. 7,622,496, the entirety of each of whichis herein incorporated by reference.

Hydrogen Atom

In some embodiments, DIM is a hydrogen atom. In some embodiments, thecovalent attachment of ubiquitin to one or more members of the IRAKkinase family (i.e., IRAK-1, -2, -3, or -4) is achieved through aprovided compound wherein DIM is a hydrogen atom. In some embodiments,upon the binding of a compound of formula I to IRAK-1, the DIM moietybeing hydrogen effectuates ubiquitination thereby marking IRAK-1 fordegradation via the Ubiquitin-Proteasome Pathway (UPP). In someembodiments, upon the binding of a compound of formula I to IRAK-2, theDIM moiety being hydrogen effectuates ubiquitination thereby markingIRAK-2 for degradation via the Ubiquitin-Proteasome Pathway (UPP). Insome embodiments, upon the binding of a compound of formula I to IRAK-3,the DIM moiety being hydrogen effectuates ubiquitination thereby markingIRAK-3 for degradation via the Ubiquitin-Proteasome Pathway (UPP). Insome embodiments, upon the binding of a compound of formula I to IRAK-4,the DIM moiety being hydrogen effectuates ubiquitination thereby markingIRAK-4 for degradation via the Ubiquitin-Proteasome Pathway (UPP).

In some embodiments, DIM is selected from those depicted in Table 1,below.

In some embodiments, the present invention provides the compound offormula I wherein DIM is a hydrogen atom, thereby forming a compound offormula I-mmm:

or a pharmaceutically acceptable salt thereof, wherein each of IRAK andL is as defined above and described in embodiments herein, both singlyand in combination.

Linker (L)

As defined above and described herein, L is a bivalent moiety thatconnects IRAK to DIM.

In some embodiments, L is a bivalent moiety that connects IRAK to DIM.In some embodiments, L is a bivalent moiety that connects IRAK to LBM.In some embodiments, L is a bivalent moiety that connects IRAK to alysine mimetic. In some embodiments, L is a bivalent moiety thatconnects IRAK to hydrogen.

In some embodiments, L is a covalent bond or a bivalent, saturated orunsaturated, straight or branched C₁₋₅₀ hydrocarbon chain, wherein 0-6methylene units of L are independently replaced by —C(D)(H)—, —C(D)₂-,—CRF—, —CF₂—, -Cy-, —O—, —N(R)—, —Si(R)₂—, —Si(OH)(R)—, —Si(OH)₂—,—P(O)(OR)—, —P(O)(R)—, —P(O)(NR₂)—, —S—, —OC(O)—, —C(O)O—, —C(O)—,—S(O)—, —S(O)₂—, —N(R)S(O)₂—, —S(O)₂N(R)—, —N(R)C(O)—, —C(O)N(R)—,—OC(O)N(R)—, —N(R)C(O)O—,

wherein: each -Cy- is independently an optionally substituted bivalentring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7membered saturated or partially unsaturated carbocyclylenyl, a 4-12membered saturated or partially unsaturated spiro carbocyclylenyl, an8-10 membered bicyclic saturated or partially unsaturatedcarbocyclylenyl, a 4-7 membered saturated or partially unsaturatedheterocyclylenyl having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, a 4-12 membered saturated or partiallyunsaturated spiro heterocyclylenyl having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclicsaturated or partially unsaturated heterocyclylenyl having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur, a5-6 membered heteroarylenyl having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclicheteroarylenyl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, and wherein r is 0, 1, 2, 3, 4, 5, 6, 7, 8,9, or 10.

In some embodiments, each -Cy- is independently an optionallysubstituted bivalent phenylenyl. In some embodiments, each -Cy- isindependently an optionally substituted 8-10 membered bicyclic arylenyl.In some embodiments, each -Cy- is independently an optionallysubstituted 4-7 membered saturated or partially unsaturatedcarbocyclylenyl. In some embodiments, each -Cy- is independently anoptionally substituted 4-12 membered saturated or partially unsaturatedspiro carbocyclylenyl. In some embodiments, each -Cy- is independentlyan optionally substituted 8-10 membered bicyclic saturated or partiallyunsaturated carbocyclylenyl. In some embodiments, each -Cy- isindependently an optionally substituted 4-7 membered saturated orpartially unsaturated heterocyclylenyl having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, each -Cy- is independently an optionally substituted 4-12membered saturated or partially unsaturated spiro heterocyclylenylhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In some embodiments, each -Cy- is independently an optionallysubstituted 8-10 membered bicyclic saturated or partially unsaturatedheterocyclylenyl having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, each -Cy- isindependently an optionally substituted 5-6 membered heteroarylenylhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In some embodiments, each -Cy- is independently an optionallysubstituted 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

In some embodiments, -Cy- is

In some embodiments, -Cy- is

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In some embodiments, -Cy- is selected from those depicted in Table 1,below.

In some embodiments, L is selected from those depicted in Table 1,below.

In some embodiments, r is 0. In some embodiments, r is 1. In someembodiments, r is 2. In some embodiments, r is 3. In some embodiments, ris 4. In some embodiments, r is 5. In some embodiments, r is 6. In someembodiments, r is 7. In some embodiments, r is 8. In some embodiments, ris 9. In some embodiments, r is 10.

In some embodiments, r is selected from those depicted in Table 1,below.

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In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments. L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is selected from those depicted in Table 1,below.

Without limitation, the point of attachment of L to IRAK and LBM can be,for example when L is

either

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein IRAK is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein IRAK is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein IRAK is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein IRAK is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein IRAK is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein IRAK is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein IRAK is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein IRAK is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein IRAK is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein IRAK is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein IRAK is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein IRAK is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein IRAK is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein IRAK is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein IRAK is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein IRAK is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein IRAK is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein IRAK is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein IRAK is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein IRAK is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein IRAK is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein IRAK is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

TABLE A Exemplified E3 ligases (LBM)

(a)

(b)

(c)

(d)

(e)

(f)

(g)

(h)

(i)

(j)

(k)

(l)

(m)

(n)

(o)

(p)

(q)

(r)

(s)

(t)

(u)

(v)

(w)

(x)

(y)

(z)

(aa)

(bb)

(cc)

(dd)

(ee)

(ff)

(gg)

(hh)

(ii)

(jj)

(kk)

(ll)

(mm)

(nn)

(oo)

(pp)

(qq)

(rr)

(ss)

(tt)

(uu)

(vv)

(ww)

(xx)

(yy)

(zz)

(aaa)

(bbb)

(ccc)

(ddd)

(eee)

(fff)

(ggg)

(hhh)

TABLE B Exemplified Linkers (L)

(1)

(2)

(3)

(4)

(5)

(6)

(7)

(8)

(9)

(10)

(11)

(12)

(13)

(14)

(15)

(16)

(17)

(18)

(19)

(20)

(21)

(22)

(23)

(24)

(25)

(26)

(27)

(28)

(29)

(30)

(31)

(32)

(33)

(34)

(35)

(36)

(37)

(38)

(39)

(40)

(41)

(42)

(43)

(44)

(45)

(46)

(47)

(49)

(50)

(51)

(52)

(53)

(54)

(55)

(56)

(57)

(58)

(59)

(60)

(61)

(62)

(63)

(64)

(65)

(66)

(67)

(68)

(69)

(70)

(71)

(72)

(73)

(74)

(75)

(76)

(77)

(78)

(79)

(80)

(81)

(82)

(83)

(84)

(85)

(86)

(87)

(88)

(89)

(90)

(91)

(92)

(93)

(94)

(95)

(96)

(97)

(98)

(99)

(100)

(101)

(102)

(103)

(104)

(105)

(106)

(107)

(108)

(109)

(110)

(111)

(112)

(113)

(114)

(115)

(116)

(117)

(118)

(119)

(120)

(121)

(122)

(123)

(124)

(125)

(126)

(127)

(128)

(129)

(130)

(131)

(132)

(133)

(134)

(135)

(136)

(137)

(138)

(139)

(140)

(141)

(142)

(143)

(144)

(145)

(146)

(147)

(148)

(149)

(150)

(151)

(152)

(153)

(154)

(155)

(156)

(157)

(158)

(159)

(160)

(161)

(162)

(163)

(164)

(165)

(166)

(167)

(168)

(169)

(170)

(171)

(172)

(173)

(174)

(175)

(176)

(177)

(178)

(179)

(180)

(181)

(182)

(183)

(184)

(185)

(186)

(187)

(188)

(189)

(190)

(191)

(192)

(193)

(194)

(195)

(196)

(197)

(198)

(199)

(200)

(201)

(202)

(203)

(204)

(205)

(206)

(207)

(208)

(209)

(210)

(211)

(212)

(213)

(214)

(215)

(216)

(217)

(218)

(219)

(220)

(221)

(222)

(223)

(224)

(225)

(226)

(227)

(228)

(229)

(230)

(231)

(232)

(233)

(234)

(235)

(236)

(237)

(238)

(239)

(240)

(241)

(242)

(243)

(244)

(245)

(246)

(247)

(248)

(249)

(250)

(251)

(253)

(254)

(255)

(256)

(257)

(258)

(259)

(260)

(261)

(262)

(263)

(264)

(265)

(266)

(267)

(268)

(269)

(270)

(271)

(272)

(273)

(274)

(275)

(276)

(277)

(278)

(279)

(280)

(281)

(282)

(283)

(284)

(285)

(286)

(287)

(288)

(289)

(290)

(291)

(292)

(293)

(294)

(295)

(296)

(297)

(298)

(299)

(300)

(301)

(302)

(303)

(304)

(305)

(306)

(307)

(308)

(309)

(310)

(311)

(312)

(313)

(314)

(315)

(316)

(317)

(318)

(319)

(320)

(321)

(322)

(323)

(324)

(325)

(326)

(327)

(328)

(329)

(330)

(331)

(332)

(333)

(334)

(335)

(336)

(337)

(338)

(339)

(340)

(341)

(342)

(343)

(344)

(345)

(346)

(347)

(348)

(349)

(350)

(351)

(352)

(353)

(354)

(355)

(356)

(357)

(358)

(359)

(360)

(361)

(362)

(363)

(364)

(365)

(366)

(367)

(368)

(369)

(370)

(371)

(372)

(373)

(374)

(375)

(376)

(377)

(378)

(379)

(380)

(381)

(382)

(383)

(384)

(385)

(386)

(387)

(388)

(389)

(390)

(391)

(392)

(393)

(394)

(395)

(396)

(397)

(398)

(399)

(400)

(401)

(402)

(403)

(404)

(405)

(406)

(407)

(408)

(409)

(410)

(411)

(412)

(413)

(414)

(415)

(416)

(417)

(418)

(419)

(420)

(421)

(422)

(423)

(424)

(425)

(426)

(427)

(428)

(429)

(430)

(431)

(432)

(433)

(434)

(435)

(436)

(437)

(438)

(438)

(439)

(440)

(441)

(442)

(443)

(444)

(445)

(446)

(447)

(448)

(449)

(450)

(451)

(452)

(453)

(454)

(455)

(456)

(457)

(458)

(459)

(460)

(461)

(462)

(463)

(464)

(465)

(466)

(467)

(468)

(469)

(470)

(471)

(472)

(473)

(474)

(475)

(475)

(476)

(477)

(478)

(479)

(480)

(481)

(482)

(483)

(484)

(485)

(486)

(487)

(488)

(489)

(490)

(491)

(492)

(493)

(494)

(495)

(496)

(497)

(498)

(499)

(500)

(501)

(502)

(503)

(504)

(505)

(506)

(507)

(508)

(509)

(510)

(511)

(512)

(513)

(514)

(515)

(516)

(517)

(518)

(519)

(520)

(521)

(522)

(523)

(524)

(525)

(526)

(527)

(528)

(529)

(530)

(531)

(532)

(533)

(534)

(535)

(536)

(537)

(538)

(539)

(540)

(541)

(542)

(543)

(544)

(545)

(546)

(547)

(548)

(549)

(550)

(551)

(552)

(553)

(554)

(555)

(556)

(557)

(558)

(559)

(560)

(561)

(562)

(563)

(564)

(565)

(566)

(567)

(568)

(569)

(570)

(571)

(572)

(573)

(574)

(575)

(576)

(577)

(578)

(579)

(580)

(581)

(582)

(583)

(584)

(585)

(586)

(587)

(588)

(589)

(590)

(591)

(592)

(593)

(594)

(595)

(596)

(597)

(598)

(599)

(600)

(601)

(602)

(603)

(604)

(605)

(606)

(607)

(608)

(609)

(610)

(611)

(612)

(613)

(614)

(615)

(616)

(617)

(618)

In some embodiments, the present invention provides a compound having anIRAK binding moiety described and disclosed herein, a LBM set forth inTable A above, and a linker set forth in Table B above, or apharmaceutically acceptable salt thereof.

Exemplary compounds of the invention are set forth in Table 1, below.

TABLE 1 Exemplary Compounds I-# Structure I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-58

I-59

I-60

I-61

I-62

I-63

I-64

I-65

In some embodiments, the present invention provides a compound set forthin Table 1, above, or a pharmaceutically acceptable salt thereof.

4. General Methods of Providing the Present Compounds

The compounds of this invention may be prepared or isolated in generalby synthetic and/or semi-synthetic methods known to those skilled in theart for analogous compounds and by methods described in detail in theExamples, herein.

In the Schemes below, where a particular protecting group, leavinggroup, or transformation condition is depicted, one of ordinary skill inthe art will appreciate that other protecting groups, leaving groups,and transformation conditions are also suitable and are contemplated.Such groups and transformations are described in detail in March'sAdvanced Organic Chemistry: Reactions, Mechanisms, and Structure, M. B.Smith and J. March, 5^(th) Edition, John Wiley & Sons, 2001,Comprehensive Organic Transformations, R. C. Larock, 2^(nd) Edition,John Wiley & Sons, 1999, and Protecting Groups in Organic Synthesis, T.W. Greene and R G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999, theentirety of each of which is hereby incorporated herein by reference.

As used herein, the phrase “oxygen protecting group” includes, forexample, carbonyl protecting groups, hydroxyl protecting groups, etc.Hydroxyl protecting groups are well known in the art and include thosedescribed in detail in Protecting Groups in Organic Synthesis, T. W.Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999, theentirety of each of which is herein incorporated by reference. Examplesof suitable hydroxyl protecting groups include, but are not limited to,esters, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkylethers, and alkoxyalkyl ethers. Examples of such esters includeformates, acetates, carbonates, and sulfonates. Specific examplesinclude formate, benzoyl formate, chloroacetate, trifluoroacetate,methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate,3-phenylpropionate, 4-oxopentanoate, 4,4-(ethylenedithio)pentanoate,pivaloate (trimethylacetyl), crotonate, 4-methoxy-crotonate, benzoate,p-benylbenzoate, 2,4,6-trimethylbenzoate, carbonates such as methyl,9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl,2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl. Examples ofsuch silyl ethers include trimethylsilyl, triethyl silyl,t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and othertrialkylsilyl ethers. Alkyl ethers include methyl, benzyl,p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, andallyloxycarbonyl ethers or derivatives. Alkoxyalkyl ethers includeacetals such as methoxymethyl, methylthiomethyl,(2-methoxyethoxy)methyl, benzyloxymethyl,beta-(trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers.Examples of arylalkyl ethers include benzyl, p-methoxybenzyl (MPM),3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl,2,6-dichlorobenzyl, p-cyanobenzyl, and 2- and 4-picolyl.

Amino protecting groups are well known in the art and include thosedescribed in detail in Protecting Groups in Organic Synthesis, T. W.Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999, theentirety of each of which is herein incorporated by reference. Suitableamino protecting groups include, but are not limited to, aralkylamines,carbamates, cyclic imides, allyl amines, amides, and the like. Examplesof such groups include t-butyloxycarbonyl (BOC), ethyloxycarbonyl,methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc),benzyloxocarbonyl (CBZ), allyl, phthalimide, benzyl (Bn),fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl,dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl,and the like.

In the schemes below, where a provided compound is formed having areactive DIM moiety (e.g., amine, alcohol, etc.), it is not shown but itis generally appreciated and well known by those having ordinary skillin the art that the reactivity of said reactive DIM moiety may be maskedby employing a suitable protecting group that can thereafter be removedin situ or during a separate synthetic step.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme 1 set forth below:

As depicted in Scheme 1, above, amine A-1 is coupled to acid A-2 usingthe coupling agent HATU in the presence of the base DIPEA in DMF to forma compound of the invention with a linker comprising an amide bond. Thesquiggly bond,

, represents the portion of the linker between IRAK and the terminalamino group of A-1 or the portion of the linker between DIM and theterminal carboxyl group of A-2, respectively. Additionally, an amidebond can be formed using coupling reagents known in the art such as, butnot limited to DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP-Cl,DEPBT, T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme 2 set forth below:

As depicted in Scheme 2, above, amine A-1 is coupled to acid A-2 usingthe coupling agent PyBOP in the presence of the base DIPEA in DMF toform a compound of the invention with a linker comprising an amide bond.The squiggly bond,

, represents the portion of the linker between IRAK and the terminalamino group of A-1 or the portion of the linker between DIM and theterminal carboxyl group of A-2, respectively. Additionally, an amidebond can be formed using coupling reagents known in the art such as, butnot limited to DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP-Cl,DEPBT, T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme 3 set forth below:

As depicted in Scheme 3, above, acid A-3 is coupled to amine A-4 usingthe coupling agent HATU in the presence of the base DIPEA in DMF to forma compound of the invention with a linker comprising an amide bond. Thesquiggly bond,

, represents the portion of the linker between IRAK and the terminalcarboxyl group of A-3 or the portion of the linker between DIM and theterminal amino group of A-4, respectively. Additionally, an amide bondcan be formed using coupling reagents known in the art such as, but notlimited to DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP-Cl, DEPBT,T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme 4 set forth below:

As depicted in Scheme 4, above, acid A-3 is coupled to amine A-4 usingthe coupling agent PyBOP in the presence of the base DIPEA in DMF toform a compound of the invention with a linker comprising an amide bond.The squiggly bond.

, represents the portion of the linker between IRAK and the terminalcarboxyl group of A-3 or the portion of the linker between DIM and theterminal amino group of A-4, respectively. Additionally, an amide bondcan be formed using coupling reagents known in the art such as, but notlimited to DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP-Cl, DEPBT,T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme 5 set forth below:

As depicted in Scheme 5, above, an S_(N)Ar displacement of fluoride A-6by amine A-5 is effected in the presence of the base DIPEA in DMF toform a compound of the invention with a linker comprising a secondaryamine. The squiggly bond,

, represents the portion of the linker between IRAK and the terminalamino group of A-5.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme 6 set forth below:

As depicted in Scheme 6, above, an S_(N)Ar displacement of fluoride A-7by amine A-8 is effected in the presence of the base DIPEA in DMF toform a compound of the invention with a linker comprising a secondaryamine. The squiggly bond,

, represents the portion of the linker between DIM and the terminalamino group of A-8.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme 7 set forth below:

As depicted in Scheme 7, above, reductive alkylation of aldehyde A-9 byamine A-10 is effected in the presence of a mild hydride source (e.g.,sodium cyanoborohydride or sodium triacetoxyborohydride) to form aprovided compound with a linker comprising a secondary amine. Thesquiggly bond,

, represents the portion of the linker between DIM and the terminalamino group of A-10.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme 8 set forth below:

As depicted in Scheme 8, above, reductive alkylation of aldehyde A-12 byamine A-11 is effected in the presence of a mild hydride source (e.g.,sodium cyanoborohydride or sodium triacetoxyborohydride) to form aprovided compound with a linker comprising a secondary amine. Thesquiggly bond,

, represents the portion of the linker between IRAK and the terminalamino group of A-11.

One of skill in the art will appreciate that various functional groupspresent in compounds of the invention such as aliphatic groups,alcohols, carboxylic acids, esters, amides, aldehydes, halogens andnitriles can be interconverted by techniques well known in the artincluding, but not limited to reduction, oxidation, esterification,hydrolysis, partial oxidation, partial reduction, halogenation,dehydration, partial hydration, and hydration. See for example, “March'sAdvanced Organic Chemistry”, 5^(th) Ed., Ed.: Smith, M. B. and March,J., John Wiley & Sons, New York: 2001, the entirety of each of which isherein incorporated by reference. Such interconversions may require oneor more of the aforementioned techniques, and certain methods forsynthesizing compounds of the invention are described below in theExemplification.

5. Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

According to another embodiment, the invention provides a compositioncomprising a compound of this invention or a pharmaceutically acceptablederivative thereof and a pharmaceutically acceptable carrier, adjuvant,or vehicle. The amount of compound in compositions of this invention issuch that it is effective to measurably degrade and/or inhibit an IRAKprotein kinase, or a mutant thereof, in a biological sample or in apatient. In certain embodiments, the amount of compound in compositionsof this invention is such that it is effective to measurably degradeand/or inhibit an IRAK protein kinase, or a mutant thereof, in abiological sample or in a patient. In certain embodiments, a compositionof this invention is formulated for administration to a patient in needof such composition. In some embodiments, a composition of thisinvention is formulated for oral administration to a patient.

The term “patient,” as used herein, means an animal, preferably amammal, and most preferably a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat may be used in the compositions of this invention include, but arenot limited to, ion exchangers, alumina, aluminum stearate, lecithin,serum proteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

A “pharmaceutically acceptable derivative” means any non-toxic salt,ester, salt of an ester or other derivative of a compound of thisinvention that, upon administration to a recipient, is capable ofproviding, either directly or indirectly, a compound of this inventionor an inhibitorily or degratorily active metabolite or residue thereof.

As used herein, the term “inhibitorily active metabolite or residuethereof” means that a metabolite or residue thereof is also an inhibitorof an IRAK protein kinase, or a mutant thereof.

As used herein, the term “degratorily active metabolite or residuethereof” means that a metabolite or residue thereof is also a degraderof an IRAK protein kinase, or a mutant thereof.

Compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic,intralesional and intracranial injection or infusion techniques.Preferably, the compositions are administered orally, intraperitoneallyor intravenously. Sterile injectable forms of the compositions of thisinvention may be aqueous or oleaginous suspension. These suspensions maybe formulated according to techniques known in the art using suitabledispersing or wetting agents and suspending agents. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent,for example as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solutionand isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium.

For this purpose, any bland fixed oil may be employed includingsynthetic mono- or diglycerides. Fatty acids, such as oleic acid and itsglyceride derivatives are useful in the preparation of injectables, asare natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, such as carboxymethyl cellulose or similar dispersingagents that are commonly used in the formulation of pharmaceuticallyacceptable dosage forms including emulsions and suspensions. Othercommonly used surfactants, such as Tweens, Spans and other emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms may also be used for the purposes of formulation.

Pharmaceutically acceptable compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, pharmaceutically acceptable compositions of thisinvention may be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

Pharmaceutically acceptable compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, provided pharmaceutically acceptablecompositions may be formulated in a suitable ointment containing theactive component suspended or dissolved in one or more carriers.Carriers for topical administration of compounds of this inventioninclude, but are not limited to, mineral oil, liquid petrolatum, whitepetrolatum, propylene glycol, polyoxyethylene, polyoxypropylenecompound, emulsifying wax and water. Alternatively, providedpharmaceutically acceptable compositions can be formulated in a suitablelotion or cream containing the active components suspended or dissolvedin one or more pharmaceutically acceptable carriers. Suitable carriersinclude, but are not limited to, mineral oil, sorbitan monostearate,polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol,benzyl alcohol and water.

For ophthalmic use, provided pharmaceutically acceptable compositionsmay be formulated as micronized suspensions in isotonic, pH adjustedsterile saline, or, preferably, as solutions in isotonic, pH adjustedsterile saline, either with or without a preservative such asbenzylalkonium chloride. Alternatively, for ophthalmic uses, thepharmaceutically acceptable compositions may be formulated in anointment such as petrolatum.

Pharmaceutically acceptable compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

Most preferably, pharmaceutically acceptable compositions of thisinvention are formulated for oral administration. Such formulations maybe administered with or without food. In some embodiments,pharmaceutically acceptable compositions of this invention areadministered without food. In other embodiments, pharmaceuticallyacceptable compositions of this invention are administered with food.

The amount of compounds of the present invention that may be combinedwith the carrier materials to produce a composition in a single dosageform will vary depending upon the host treated, the particular mode ofadministration. Preferably, provided compositions should be formulatedso that a dosage of between 0.01-100 mg/kg body weight/day of thecompound can be administered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of a compound of the present invention in the composition willalso depend upon the particular compound in the composition.

Uses of Compounds and Pharmaceutically Acceptable Compositions

Compounds and compositions described herein are generally useful for thedegradation and/or inhibition of kinase activity of one or more enzymes.

Examples of kinases that are degraded and/or inhibited by the compoundsand compositions described herein and against which the methodsdescribed herein are useful include those of the interleukin-1receptor-associated kinase (IRAK) family of kinases, the members ofwhich include IRAK-1, IRAK-2, and IRAK-4, or a mutant thereof. Li etal., “IRAK-4: A novel member of the IRAK family with the properties ofan IRAK-kinase.” PNAS 2002, 99(8), 5567-5572, Flannery et al., “Theinterleukin-1 receptor-associated kinases: Critical regulators of innateimmune signaling” Biochem Pharm 2010, 80(12), 1981-1991 incorporated byreference in its entirety.

The activity of a compound utilized in this invention as a degraderand/or inhibitor of IRAK-1, IRAK-2, and/or IRAK-4, or a mutant thereof,may be assayed in vitro, in vivo or in a cell line. In vitro assaysinclude assays that determine inhibition of either the phosphorylationactivity and/or the subsequent functional consequences, or ATPaseactivity of activated IRAK-1, IRAK-2, and/or IRAK-4, or a mutantthereof. Alternate in vitro assays quantitate the ability of theinhibitor to bind to IRAK-1, IRAK-2 and/or IRAK-4. Inhibitor binding maybe measured by radiolabeling the inhibitor prior to binding, isolatingthe inhibitor/IRAK-1, inhibitor/IRAK-2, or inhibitor/IRAK-4 complex anddetermining the amount of radiolabel bound. Alternatively, inhibitorbinding may be determined by running a competition experiment where newinhibitors are incubated with IRAK-1, IRAK-2, and/or IRAK-4 bound toknown radioligands. Representative in vitro and in vivo assays useful inassaying an IRAK-4 inhibitor include those described and disclosed in,e.g., Kim et al., “A critical role for IRAK4 kinase activity inToll-like receptor-mediated innate immunity,” J. Exp. Med. 2007 204(5),1025-1036; Lebakken et al., “A Fluorescence Lifetime Based Binding Assayto Characterize Kinase Inhibitors,” J. Biomol. Screen. 2007, 12(6),828-841; Maschera et al., “Overexpression of an enzymatically inactiveinterleukin-1-receptor-associated kinase activates nuclear factor-κB,”Biochem. J. 1999, 339, 227-231; Song et al., “The kinase activities ofinterleukin-e receptor associated kinase (IRAK)-1 and 4 are redundant inthe control of inflammatory cytokine expression in human cells,” Mol.Immunol. 2009, 46, 1458-1466, each of, the entirety of each of which isherein incorporated by reference. Detailed conditions for assaying acompound utilized in this invention as a degrader and/or inhibitor ofIRAK-1, IRAK-2, and/or IRAK-4, or a mutant thereof, are set forth in theExamples below.

The best characterized member of the IRAK family is the serine/threoninekinase IRAK-4. IRAK-4 is implicated in signaling innate immune responsesfrom Toll-like receptors (TLRs) and Toll/IL-1 receptors (TIRs).

Innate immunity detects pathogens through the recognition ofpathogen-associated molecular patterns by TLRs, when then links to theadaptive immune response. TLRs recognize conserved structures of bothmicrobes and endogenous molecules. TLRs which recognize bacterial andfungal components are located on the cell surface, whereas TLRs whichrecognize viral or microbial nucleic acids are localized tointracellular membranes such as endosomes and phagosomes. Cell surfaceTLRs can be targeted by small molecules and antibodies, whereasintracellular TLRs require targeting with oligonucleotides.

TLRs mediate the innate immune response by upregulating the expressionof inflammatory genes in multiple target cells. See, e.g., Sen et al.,“Transcriptional signaling by double-stranded RNA: role of TLR3,”Cytokine & Growth Factor Rev. 2005, 16, 1-14, incorporated by referencein its entirety. While TLR-mediated inflammatory response is criticalfor innate immunity and host defense against infections, uncontrolledinflammation is detrimental to the host leading to sepsis and chronicinflammatory diseases, such as chronic arthritis, atherosclerosis,multiple sclerosis, cancers, autoimmune disorders such as rheumatoidarthritis, lupus, asthma, psoriasis, and inflammatory bowel diseases.

Upon binding of a ligand, most TLRs recruit the adaptor molecule MyD88through the TIR domain, mediating the MyD88-dependent pathway. MyD88then recruits IRAK-4, which engages with the nuclear factor-κB (NF-κB),mitogen-activated protein (MAP) kinase and interferon-regulatory factorcascades and leads to the induction of pro-inflammatory cytokines. Theactivation of NF-κB results in the induction of inflammatory cytokinesand chemokines, such as TNF-α, IL-1α, IL-6 and IL-8. The kinase activityof IRAK-4 has been shown to play a critical role in the TLR-mediatedimmune and inflammatory responses. IRAK4 is a key mediator of the innateimmune response orchestrated by interleukin-1 receptor (IL-1R),interleukin-18 receptor (IL-18R), IL-33 receptor (IL-33R), and Toll-likereceptors (TLRs). Inactivation of IRAK-1 and/or IRAK-4 activity has beenshown to result in diminished production of cytokines and chemokines inresponse to stimulation of IL-1 and TLR ligands. See, e.g., Picard etal., “Clinical features and outcome of patients with IRAK-4 and MyD88deficiency,” Medicine (Baltimore), 2010, 89(6), 043-25; Li, “IRAK4 inTLR/IL-1R signaling: Possible clinical applications,” Eur. J. Immunology2008, 38:614-618; Cohen et al., “Targeting protein kinases for thedevelopment of anti-inflammatory drugs,” Curr. Opin. Cell Bio. 2009,21:317-324; Flannery et al., “The interleukin-1 receptor-associatedkinases: Critical regulators of innate immune signalling,” Biochem.Pharm. 2010, 80(12), 1981-1991; Gottipati et al., “IRAK1: A criticalsignaling mediator of innate immunity,” Cellular Signaling 2008, 20,269-276; Kim et al., “A critical role for IRAK4 kinase activity inToll-like receptor-mediated innate immunity,” J. Exp. Med. 2007 204(5),1025-1036; Koziczak-Holbro et al., “IRAK-4 Kinase Activity Is Requiredfor Interleukin-1 (IL-1) Receptor- and Toll-like Receptor 7-mediatedSignaling and Gene Expression,” J. Biol. Chem. 2007, 282(18),13552-13560; Kubo-Murai et al., “IRAK-4-dependent Degradation of IRAK-1is a Negative Feedback Signal for TLR-mediated NF-κB Activation.” J.Biochem. 2008, 143, 295-302; Maschera et al., “Overexpression of anenzymatically inactive interleukin-1-receptor-associated kinaseactivates nuclear factor-κB,” Biochem. J. 1999, 339, 227-231; Lin etal., “Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1Rsignalling,” Nature 2010, 465(17), 885-891; Suzuki et al., “IRAK-4 asthe central TIR signaling mediator in innate immunity,” TRENDS inImmunol. 2002, 23(10), 503-506; Suzuki et al., “Severe impairment ofinterleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4,”Nature 2002, 416, 750-754; Swantek et al., “IL-1 Receptor-AssociatedKinase Modulates Host Responsiveness to Endotoxin,” J. Immunol. 2000,164, 4301-4306; Hennessy, E., et al., “Targeting Toll-like receptors:emerging therapeutics?” Nature Reviews, vol. 9, pp: 293-307 (2010);Dinarello, C. “Interleukin-18 and the Pathogenesis of InflammatoryDiseases,” Seminars in Nephrology, vol. 27, no. 1, pp: 98-114 (2007),each of, the entirety of each of which is herein incorporated byreference. In fact, knockdown mice that express a catalytically inactivemutant IRAK-4 protein are completely resistant to septic shock and showimpaired IL-1 activity. Moreover, these mice are resistant to joint andbone inflammation/destruction in an arthritis model, suggesting thatIRAK-4 may be targeted to treat chronic inflammation. Further, whileIRAK-4 appears to be vital for childhood immunity against some pyogenicbacteria, it has been shown to play a redundant role in protectiveimmunity to most infections in adults, as demonstrated by one study inwhich patients older than 14 lacking IRAK-4 activity exhibited noinvasive infections. Cohen et al., “Targeting protein kinases for thedevelopment of anti-inflammatory drugs,” Curr. Opin. Cell Bio. 2009,21:317-324; Ku et al., “Selective predisposition to bacterial infectionsin IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwiseredundant in protective immunity,” J. Exp. Med. 2007, 204(10),2407-2422; Picard et al., “Inherited human IRAK-4 deficiency: anupdate,” Immunol. Res. 2007, 38, 347-352; Song et al., “The kinaseactivities of interleukin-e receptor associated kinase (IRAK)-1 and 4are redundant in the control of inflammatory cytokine expression inhuman cells,” Mol. Immunol. 2009, 46, 1458-1466; Rokosz, L. et al.,“Kinase inhibitors as drugs for chronic inflammatory and immunologicaldiseases: progress and challenges,” Expert Opinions on TherapeuticTargets, 12(7), pp: 883-903 (2008); Gearing, A. “Targeting toll-likereceptors for drug development: a summary of commercial approaches,”Immunology and Cell Biology, 85, pp: 490-494 (2007); Dinarello, C.“IL-1: Discoveries, controversies and future directions,” EuropeanJournal of Immunology, 40, pp: 595-653 (2010), each of, the entirety ofeach of which is herein incorporated by reference. Because TLRactivation triggers IRAK-4 kinase activity, IRAK-4 inhibition presentsan attractive target for treating the underlying causes of inflammationin countless diseases.

Representative IRAK-4 inhibitors include those described and disclosedin e.g., Buckley et al., Bioorg. Med. Chem. Lett. 2008, 18, 3211-3214;Buckley et al., Bioorg. Med. Chem. Lett. 2008, 18, 3291-3295; Buckley etal., Bioorg. Med. Chem. Lett. 2008, 18, 3656-3660; Powers et al.,“Discovery and initial SAR of inhibitors of interleukin-1receptor-associated kinase-4,” Bioorg. Med. Chem. Lett. 2006, 16,2842-2845; Wng et al., “IRAK-4 Inhibitors for Inflammation,” Curr.Topics in Med. Chem. 2009, 9, 724-737, each of, the entirety of each ofwhich is herein incorporated by reference.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease or disorder, or one or more symptoms thereof, asdescribed herein. In some embodiments, treatment may be administeredafter one or more symptoms have developed. In other embodiments,treatment may be administered in the absence of symptoms. For example,treatment may be administered to a susceptible individual prior to theonset of symptoms (e.g., in light of a history of symptoms and/or inlight of genetic or other susceptibility factors). Treatment may also becontinued after symptoms have resolved, for example to prevent or delaytheir recurrence.

Provided compounds are degraders and/or inhibitors of one of more ofIRAK-1, IRAK-2, and/or IRAK-4 and are therefore useful for treating oneor more disorders associated with activity of one or more ofIRAK-1,IRAK-2, and/or IRAK-4. Thus, in certain embodiments, the presentinvention provides a method for treating a IRAK-1-mediated, aIRAK-2-mediated, and/or a IRAK-4-mediated disorder comprising the stepof administering to a patient in need thereof a compound of the presentinvention, or pharmaceutically acceptable composition thereof.

As used herein, the terms “IRAK-1-mediated”, “IRAK-2-mediated”, and/or“IRAK-4-mediated” disorders, diseases, and/or conditions as used hereinmeans any disease or other deleterious condition in which one or more ofIRAK-1, IRAK-2, and/or IRAK-4, or a mutant thereof, are known to play arole. Accordingly, another embodiment of the present invention relatesto treating or lessening the severity of one or more diseases in whichone or more of IRAK-1, IRAK-2, and/or IRAK-4, or a mutant thereof, areknown to play a role.

In some embodiments, the present invention provides a method fortreating one or more disorders, diseases, and/or conditions wherein thedisorder, disease, or condition is a cancer, a neurodegenative disorder,a viral disease, an autoimmune disease, an inflammatory disorder, ahereditary disorder, a hormone-related disease, a metabolic disorder,conditions associated with organ transplantation, immunodeficiencydisorders, a destructive bone disorder, a proliferative disorder, aninfectious disease, a condition associated with cell death,thrombin-induced platelet aggregation, liver disease, pathologic immuneconditions involving T cell activation, a cardiovascular disorder, or aCNS disorder.

Diseases and conditions treatable according to the methods of thisinvention include, but are not limited to, cancer (see, e.g., Ngo, V. etal., “Oncogenically active MYD88 mutations in human lymphoma,” Nature,vol. 000, pp: 1-7 (2010); Lust, J. et al., “Induction of a ChronicDisease State in patients With Smoldering of Indolent Multiple Myelomaby Targeting Interleukin 1β-Induced Interleukin 6 Production and theMyeloma Proliferative Component,” Mayo Clinic Proceedings, 84(2), pp:114-122 (2009)), diabetes, cardiovascular disease, viral disease,autoimmune diseases such as lupus (see, e.g., Dinarello, C.“Interleukin-18 and the Pathogenesis of Inflammatory Diseases,” Seminarsin Nephrology, vol. 27, no. 1, pp: 98-114 (2007); Cohen et al.,“Targeting protein kinases for the development of anti-inflammatorydrugs,” Curr. Opin. Cell Bio. 2009, 21:317-324) and rheumatoid arthritis(see, e.g., Geyer, M. et al., “Actual status of antiinterleukin-1therapies in rheumatic diseases,” Current Opinion in Rheumatology, 22,pp: 246-251 (2010)), autoinflammatory syndromes (see, e.g., Hoffman, H.et al., “Efficacy and Safety of Rilonacept (Interleukin-1 Trap) inPatients with Cryopyrin-Associated Periodic Syndromes,” Arthritis &Rheumatism, vol. 58, no. 8, pp: 2443-2452 (2008)), atherosclerosis,psoriasis, allergic disorders, inflammatory bowel disease (see, e.g.,Cario, E. “Therapeutic Impact of Toll-like Receptors on InflammatoryBowel Diseases: A Multiple-edged Sword,” Inflamm. Bowel Dis., 14, pp:411-421 (2008)), inflammation (see, e.g., Dinarello, C. “Interleukin 1and interleukin 18 as mediators of inflammation and the aging process,”The American Journal of Clinical Nutrition, 83, pp: 447S-455S (2006)),acute and chronic gout and gouty arthritis (see. e.g., Terkeltaub, R.“Update on gout: new therapeutic strategies and options,” Nature, vol.6, pp: 30-38 (2010); Weaver, A. “Epidemiology of gout,” Cleveland ClinicJournal of Medicine, vol. 75, suppl. 5, pp: S9-S12 (2008); Dalbeth, N.et al., “Hyperuricaemia and gout: state of the art and futureperspectives,” Annals of Rheumatic Diseases, 69, pp: 1738-1743 (2010);Martinon, F. et al., “Gout-associated uric acid crystals activate theNALP3 inflammasome,” Nature, vol. 440, pp: 237-241 (2006); So, A. etal., “A pilot study of IL-1 inhibition by anakinra in acute gout.”Arthritis Research & Therapy, vol. 9, no. 2, pp: 1-6 (2007); Terkeltaub,R. et al., “The interleukin 1 inhibitor rilonacept in treatment ofchronic gouty arthritis: results of a placebo-controlled, monosequencecrossover, non-randomised, single-blind pilot study,” Annals ofRheumatic Diseases, 68, pp: 1613-1617 (2009); Torres, R. et al.,“Hyperalgesia, synovitis and multiple biomarkers of inflammation aresuppressed by interleukin 1 inhibition in a novel animal model of goutyarthritis,” Annals of Rheumatic Diseases, 68, pp: 1602-1608 (2009)),neurological disorders, metabolic syndrome (see, e.g., Troseid, M. “Therole of interleukin-18 in the metabolic syndrome,” CardiovascularDiabetology, 9:11, pp: 1-8 (2010)), immunodeficiency disorders such asAIDS and HIV (see, e.g., Iannello, A. et al., “Role of Interleukin-18 inthe Development and Pathogenesis of AIDS,” AIDS Reviews, 11, pp: 115-125(2009)), destructive bone disorders (see, e.g., Hennessy, E., et al.,“Targeting Toll-like receptors: emerging therapeutics?” Nature Reviews,vol. 9, pp: 293-307 (2010)), osteoarthritis, proliferative disorders,Waldenström's Macroglobulinemia (see, e.g., Treon, et al., “Whole genomesequencing reveals a widely expressed mutation (MYD88 L265P) withoncogenic activity in Waldenström's Macroglobulinemia” 53^(rd) ASHAnnual Meeting; Xu, et al., “A somatic variant in MYD88 (L256P) revealedby whole genome sequencing differentiates lymphoplasmacytic lymphomafrom marginal zone lymphomas” 53^(rd) ASH Annual Meeting; Yang et al.,“Disruption of MYD88 pathway signaling leads to loss of constitutiveIRAK1, NK-kB and JAK/STAT signaling and induces apoptosis of cellsexpressing the MYD88 L265P mutation in Waldenström's Macroglobulinemia”53^(rd) ASH Annual Meeting; Iriyama et al., “Clinical significance ofgenetic mutations of CD79B, CARD11, MYD88, and EZH2 genes in diffuselarge B-cell lymphoma patients” 53^(rd) ASH Annual Meeting; infectiousdiseases, conditions associated with cell death, pathologic immuneconditions involving T cell activation, and CNS disorders in a patient.In one embodiment, a human patient is treated with a compound of thecurrent invention and a pharmaceutically acceptable carrier, adjuvant,or vehicle, wherein said compound is present in an amount to measurablydegrade and/or inhibit IRAK-1 only, IRAK-2-only, IRAK-4-only and/orIRAK1 and IRAK4 kinase activity.

Compounds of the current invention are useful in the treatment of aproliferative disease selected from a benign or malignant tumor, solidtumor, carcinoma of the brain, kidney, liver, adrenal gland, bladder,breast, stomach, gastric tumors, ovaries, colon, rectum, prostate,pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus,larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas,multiple myeloma, gastrointestinal cancer, especially colon carcinoma orcolorectal adenoma, a tumor of the neck and head, an epidermalhyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, aneoplasia of epithelial character, adenoma, adenocarcinoma,keratoacanthoma, epidermoid carcinoma, large cell carcinoma,non-small-cell lung carcinoma, lymphomas, Hodgkins and Non-Hodgkins, amammary carcinoma, follicular carcinoma, undifferentiated carcinoma,papillary carcinoma, seminoma, melanoma, an IL-1 driven disorder, anMyD88 driven disorder, Smoldering of indolent multiple myeloma, orhematological malignancies (including leukemia, diffuse large B-celllymphoma (DLBCL), ABC DLBCL, chronic lymphocytic leukemia (CLL), chroniclymphocytic lymphoma, primary effusion lymphoma, Burkittlymphoma/leukemia, acute lymphocytic leukemia, B-cell prolymphocyticleukemia, lymphoplasmacytic lymphoma, Waldenström's macroglobulinemia(WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma,intravascular large B-cell lymphoma, AML, MDS).

In some embodiments the proliferative disease which can be treatedaccording to the methods of this invention is an MyD88 driven disorder.In some embodiments, the MyD88 driven disorder which can be treatedaccording to the methods of this invention is selected from ABC DLBCL,primary CNS lymphomas, primary extranodal lymphomas, Waldenström'smacroglobulinemia, Hodgkin's lymphoma, primary cutaneous T-cell lymphomaand chronic lymphocytic leukemia.

In some embodiments the proliferative disease which can be treatedaccording to the methods of this invention is an IL-1 driven disorder.In some embodiments the IL-1 driven disorder is Smoldering of indolentmultiple myeloma.

Compounds according to the invention are useful in the treatment ofinflammatory or obstructive airways diseases, resulting, for example, inreduction of tissue damage, airways inflammation, bronchialhyperreactivity, remodeling or disease progression. Inflammatory orobstructive airways diseases to which the present invention isapplicable include asthma of whatever type or genesis including bothintrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mildasthma, moderate asthma, severe asthma, bronchitic asthma,exercise-induced asthma, occupational asthma and asthma inducedfollowing bacterial infection. Treatment of asthma is also to beunderstood as embracing treatment of subjects, e.g. of less than 4 or 5years of age, exhibiting wheezing symptoms and diagnosed or diagnosableas “wheezy infants”, an established patient category of major medicalconcern and now often identified as incipient or early-phase asthmatics.

Compounds according to the invention are useful in the treatment ofheteroimmune diseases. Examples of such heteroimmune diseases include,but are not limited to, graft versus host disease, transplantation,transfusion, anaphylaxis, allergies (e.g., allergies to plant pollens,latex, drugs, foods, insect poisons, animal hair, animal dander, dustmites, or cockroach calyx), type I hypersensitivity, allergicconjunctivitis, allergic rhinitis, and atopic dermatitis.

Prophylactic efficacy in the treatment of asthma will be evidenced byreduced frequency or severity of symptomatic attack, e.g. of acuteasthmatic or bronchoconstrictor attack, improvement in lung function orimproved airways hyperreactivity. It may further be evidenced by reducedrequirement for other, symptomatic therapy, such as therapy for orintended to restrict or abort symptomatic attack when it occurs, forexample antiinflammatory or bronchodilatory. Prophylactic benefit inasthma may in particular be apparent in subjects prone to “morningdipping”. “Morning dipping” is a recognized asthmatic syndrome, commonto a substantial percentage of asthmatics and characterised by asthmaattack, e.g. between the hours of about 4 to 6 am, i.e. at a timenormally substantially distant form any previously administeredsymptomatic asthma therapy.

Compounds of the current invention can be used for other inflammatory orobstructive airways diseases and conditions to which the presentinvention is applicable and include acute lung injury (ALI), adult/acuterespiratory distress syndrome (ARDS), chronic obstructive pulmonary,airways or lung disease (COPD, COAD or COLD), including chronicbronchitis or dyspnea associated therewith, emphysema, as well asexacerbation of airways hyperreactivity consequent to other drugtherapy, in particular other inhaled drug therapy. The invention is alsoapplicable to the treatment of bronchitis of whatever type or genesisincluding, but not limited to, acute, arachidic, catarrhal, croupus,chronic or phthinoid bronchitis. Further inflammatory or obstructiveairways diseases to which the present invention is applicable includepneumoconiosis (an inflammatory, commonly occupational, disease of thelungs, frequently accompanied by airways obstruction, whether chronic oracute, and occasioned by repeated inhalation of dusts) of whatever typeor genesis, including, for example, aluminosis, anthracosis, asbestosis,chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis.

With regard to their anti-inflammatory activity, in particular inrelation to inhibition of eosinophil activation, compounds of theinvention are also useful in the treatment of eosinophil relateddisorders, e.g. eosinophilia, in particular eosinophil related disordersof the airways (e.g. involving morbid eosinophilic infiltration ofpulmonary tissues) including hypereosinophilia as it effects the airwaysand/or lungs as well as, for example, eosinophil- related disorders ofthe airways consequential or concomitant to Loffler's syndrome,eosinophilic pneumonia, parasitic (in particular metazoan) infestation(including tropical eosinophilia), bronchopulmonary aspergillosis,polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilicgranuloma, eosinophilic asthma, eosinophilic COPD, andeosinophil-related disorders affecting the airways occasioned bydrug-reaction.

Compounds of the invention are also useful in the treatment ofinflammatory or allergic conditions of the skin, for example psoriasis,generalized pustular psoriasis (GPP), psoriasis vulgaris, contactdermatitis, atopic dermatitis, alopecia areata, erythema multiforma,dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivityangiitis, urticaria, bullous pemphigoid, lupus erythematosus, systemiclupus erythematosus, pemphigus vulgaris, pemphigus foliaceus,paraneoplastic pemphigus, epidermolysis bullosa acquisita, acnevulgaris, hidradenitis suppurativa, Sweet Syndrome, pyodermagangrenosum, and other inflammatory or allergic conditions of the skin.

Compounds of the invention may also be used for the treatment of otherdiseases or conditions, such as diseases or conditions having aninflammatory component, for example, treatment of diseases andconditions of the eye such as ocular allergy, conjunctivitis,keratoconjunctivitis sicca, and vernal conjunctivitis, diseasesaffecting the nose including allergic rhinitis, and inflammatory diseasein which autoimmune reactions are implicated or having an autoimmunecomponent or etiology, including autoimmune hematological disorders(e.g. hemolytic anemia, aplastic anemia, pure red cell anemia andidiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoidarthritis, polychondritis, scleroderma, Wegener granulamatosis,dermatomyositis, chronic active hepatitis, myasthenia gravis,Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory boweldisease (e.g. ulcerative colitis and Crohn's disease), irritable bowelsyndrome, celiac disease, periodontitis, hyaline membrane disease,kidney disease, glomerular disease, alcoholic liver disease, multiplesclerosis, endocrine opthalmopathy, Grave's disease, sarcoidosis,alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis,primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren'ssyndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis,interstitial lung fibrosis, psoriatic arthritis, systemic juvenileidiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis,vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis(with and without nephrotic syndrome, e.g. including idiopathicnephrotic syndrome or minal change nephropathy), chronic granulomatousdisease, endometriosis, leptospiriosis renal disease, glaucoma, retinaldisease, ageing, headache, pain, complex regional pain syndrome, cardiachypertrophy, musclewasting, catabolic disorders, obesity, fetal growthretardation, hyperchlolesterolemia, heart disease, chronic heartfailure, mesothelioma, anhidrotic ecodermal dysplasia, Behcet's disease,incontinentia pigmenti, Paget's disease, pancreatitis, hereditaryperiodic fever syndrome, asthma (allergic and non-allergic, mild,moderate, severe, bronchitic, and exercise-induced), acute lung injury,acute respiratory distress syndrome, eosinophilia, hypersensitivities,anaphylaxis, nasal sinusitis, ocular allergy, silica induced diseases,COPD (reduction of damage, airways inflammation, bronchialhyperreactivity, remodeling or disease progression), pulmonary disease,cystic fibrosis, acid-induced lung injury, pulmonary hypertension,polyneuropathy, cataracts, muscle inflammation in conjunction withsystemic sclerosis, inclusion body myositis, myasthenia gravis,thyroiditis, Addison's disease, lichen planus, Type 1 diabetes, or Type2 diabetes, appendicitis, atopic dermatitis, asthma, allergy,blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis,cholangitis, cholecystitis, chronic graft rejection, colitis,conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis,dermatomyositis, encephalitis, endocarditis, endometritis, enteritis,enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis,gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis,hidradenitis suppurativa, immunoglobulin A nephropathy, interstitiallung disease, laryngitis, mastitis, meningitis, myelitis myocarditis,myositis, nephritis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis,prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis,stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis,uveitis, vaginitis, vasculitis, or vulvitis.

In some embodiments the inflammatory disease which can be treatedaccording to the methods of this invention is an disease of the skin. Insome embodiments, the inflammatory disease of the skin is selected fromcontact dermatitits, atopic dermatitis, alopecia areata, erythemamultiforma, dermatitis herpetiformis, scleroderma, vitiligo,hypersensitivity angiitis, urticaria, bullous pemphigoid, pemphigusvulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysisbullosa acquisita, hidradenitis suppurativa, and other inflammatory orallergic conditions of the skin.

In some embodiments the inflammatory disease which can be treatedaccording to the methods of this invention is selected from acute andchronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis,rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenileidiopathic arthritis (SJIA), cryopyrin associated periodic syndrome(CAPS), adult onset Still's disease, macrophage activation syndrome(MAS), primary and secondary hemophagocytic lymphohistiocytosis (HLH),familial mediterranean fever, NLRP12 autoinflammatory syndrome, andosteoarthritis.

In some embodiments the inflammatory disease which can be treatedaccording to the methods of this invention is a TH17 mediated disease.In some embodiments the TH17 mediated disease is selected from systemiclupus erythematosus, multiple sclerosis, psoriasis vulgaris,hidradenitis suppurativa, and inflammatory bowel disease (includingCrohn's disease or ulcerative colitis).

In some embodiments the inflammatory disease which can be treatedaccording to the methods of this invention is selected from Sjogren'ssyndrome, allergic disorders, osteoarthritis, conditions of the eye suchas ocular allergy, conjunctivitis, keratoconjunctivitis sicca and vernalconjunctivitis, and diseases affecting the nose such as allergicrhinitis or chronic rhinosinusitis with nasal polyps (CRSwNP).

In some embodiments, the present invention provides a method of treatinghidradenitis suppurativa in a patient in need thereof, comprisingadministering a compound of the present invention, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the present invention provides a method of treatingatopic dermatitis in a patient in need thereof, comprising administeringa compound of the present invention, or a pharmaceutically acceptablesalt thereof.

In some embodiments, the present invention provides a method of treatingrheumatoid arthritis in a patient in need thereof, comprisingadministering a compound of the present invention, or a pharmaceuticallyacceptable salt thereof.

Cardiovascular diseases which can be treated according to the methods ofthis invention include, but are not limited to, restenosis,cardiomegaly, atherosclerosis, myocardial infarction, ischemic stroke,congestive heart failure, angina pectoris, reocclusion afterangioplasty, restenosis after angioplasty, reocclusion afteraortocoronary bypass, restenosis after aortocoronary bypass, stroke,transitory ischemia, a peripheral arterial occlusive disorder, pulmonaryembolism, and deep venous thrombosis.

In some embodiments, the neurodegenerative disease which can be treatedaccording to the methods of this invention include, but are not limitedto, Alzheimer's disease, Parkinson's disease, amyotrophic lateralsclerosis, Huntington's disease, cerebral ischemia, andneurodegenerative disease caused by traumatic injury, glutamateneurotoxicity, hypoxia, epilepsy, treatment of diabetes, metabolicsyndrome, obesity, organ transplantation and graft versus host disease.

The loss of IRAK4 function results in decreased A3 levels in an in vivomurine model of Alzheimer's disease and was associated with diminishedmicrogliosis and astrogliosis in aged mice. Analysis of microgliaisolated from the adult mouse brain revealed an altered pattern of geneexpression associated with changes in microglial phenotype that wereassociated with expression of IRF transcription factors that governmicroglial phenotype. Further, loss of IRAK4 function also promotedamyloid clearance mechanisms, including elevated expression ofinsulin-degrading enzyme. Finally, blocking IRAK function restoredolfactory behavior (Cameron et al. “Loss of InterleukinReceptor-Associated Kinase 4 Signaling Suppresses Amyloid Pathology andAlters Microglial Phenotype in a Mouse Model of Alzheimer's Disease”Journal of Neuroscience (2012) 32(43), 15112-15123).

In some embodiments the invention provides a method of treating,preventing or lessening the severity of Alzheimer's disease comprisingadministering to a patient in need thereof a provided compound or apharmaceutically acceptable salt or composition thereof.

In some embodiments the invention provides a method of treating adisease condition commonly occurring in connection with transplantation.In some embodiments, the disease or condition commonly occurring inconnection with transplantation is selected from organ transplantation,organ transplant rejection, and graft versus host disease.

In some embodiments the invention provides a method of treating ametabolic disease. In some embodiments the metabolic disease is selectedfrom Type 1 diabetes, Type 2 diabetes, metabolic syndrome, and obesity.

In some embodiments the invention provides a method of treating a viraldisease. In some embodiments, the viral infection is HIV infection.

Furthermore, the invention provides the use of a compound according tothe definitions herein, or a pharmaceutically acceptable salt, or ahydrate or solvate thereof for the preparation of a medicament for thetreatment of a proliferative disease, an inflammatory disease, anobstructive respiratory disease, a cardiovascular disease, a metabolicdisease, a neurological disease, a neurodegenerative disease, a viraldisease, or a disorder commonly occurring in connection withtransplantation.

Multiple Degradation

In some embodiments, the invention provides compounds that modulatetargeted ubiquitination and degradation of one or more IRAK kinase. Insome embodiments, a provided compound modulates targeted ubiquitinationand degradation of one or more IRAK kinase and one or more additionalprotein. In some instances, a provided compound modulates targetedubiquitination and degradation of IRAK4 and one, two, three, four, orfive additional proteins.

In certain embodiments, the invention provides compounds that are tripledegraders.

Combination Therapies

Depending upon the particular condition, or disease, to be treated,additional therapeutic agents, which are normally administered to treatthat condition, may be administered in combination with compounds andcompositions of this invention. As used herein, additional therapeuticagents that are normally administered to treat a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated.”

In certain embodiments, a provided combination, or composition thereof,is administered in combination with another therapeutic agent.

In some embodiments, the present invention provides a method of treatinga disclosed disease or condition comprising administering to a patientin need thereof an effective amount of a compound disclosed herein or apharmaceutically acceptable salt thereof and co-administeringsimultaneously or sequentially an effective amount of one or moreadditional therapeutic agents, such as those described herein. In someembodiments, the method includes co-administering one additionaltherapeutic agent. In some embodiments, the method includesco-administering two additional therapeutic agents. In some embodiments,the combination of the disclosed compound and the additional therapeuticagent or agents acts synergistically.

Examples of agents the combinations of this invention may also becombined with include, without limitation: treatments for Alzheimer'sDisease such as Aricept® and Excelon®; treatments for HIV such asritonavir; treatments for Parkinson's Disease such as L-DOPA/carbidopa,entacapone, ropinrole, pramipexole, bromocriptine, pergolide,trihexephendyl, and amantadine; agents for treating Multiple Sclerosis(MS) such as beta interferon (e.g., Avonex® and Rebif®), Copaxone®, andmitoxantrone; treatments for asthma such as albuterol and Singulair®;agents for treating schizophrenia such as zyprexa, risperdal, seroquel,and haloperidol; anti-inflammatory agents such as corticosteroids, TNFblockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine;immunomodulatory and immunosuppressive agents such as cyclosporin,tacrolimus, rapamycin, mycophenolate mofetil, interferons,corticosteroids, cyclophophamide, azathioprine, and sulfasalazine;neurotrophic factors such as acetylcholinesterase inhibitors, MAOinhibitors, interferons, anti-convulsants, ion channel blockers,riluzole, and anti-Parkinsonian agents; agents for treatingcardiovascular disease such as beta-blockers, ACE inhibitors, diuretics,nitrates, calcium channel blockers, and statins; agents for treatingliver disease such as corticosteroids, cholestyramine, interferons, andanti-viral agents; agents for treating blood disorders such ascorticosteroids, anti-leukemic agents, and growth factors; agents thatprolong or improve pharmacokinetics such as cytochrome P450 inhibitors(i.e., inhibitors of metabolic breakdown) and CYP3A4 inhibitors (e.g.,ketokenozole and ritonavir), and agents for treating immunodeficiencydisorders such as gamma globulin.

In certain embodiments, combination therapies of the present invention,or a pharmaceutically acceptable composition thereof, are administeredin combination with a monoclonal antibody or an siRNA therapeutic.

Those additional agents may be administered separately from a providedcombination therapy, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a compound of this invention in a single composition. Ifadministered as part of a multiple dosage regime, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another normally within five hours from one another.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with this invention. For example, a combination ofthe present invention may be administered with another therapeutic agentsimultaneously or sequentially in separate unit dosage forms or togetherin a single unit dosage form.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

One or more other therapeutic agent may be administered separately froma compound or composition of the invention, as part of a multiple dosageregimen. Alternatively, one or more other therapeutic agents may be partof a single dosage form, mixed together with a compound of thisinvention in a single composition. If administered as a multiple dosageregime, one or more other therapeutic agent and a compound orcomposition of the invention may be administered simultaneously,sequentially or within a period of time from one another, for examplewithin 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,18, 20, 21, 22, 23, or 24 hours from one another. In some embodiments,one or more other therapeutic agent and a compound or composition of theinvention are administered as a multiple dosage regimen within greaterthan 24 hours a parts.

In one embodiment, the present invention provides a compositioncomprising a provided compound or a pharmaceutically acceptable saltthereof and one or more additional therapeutic agents. The therapeuticagent may be administered together with a provided compound or apharmaceutically acceptable salt thereof, or may be administered priorto or following administration of a provided compound or apharmaceutically acceptable salt thereof. Suitable therapeutic agentsare described in further detail below. In certain embodiments, aprovided compound or a pharmaceutically acceptable salt thereof may beadministered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16hours, 17 hours, or 18 hours before the therapeutic agent. In otherembodiments, a provided compound or a pharmaceutically acceptable saltthereof may be administered up to 5 minutes, 10 minutes, 15 minutes, 30minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours,8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15hours, 16 hours, 17 hours, or 18 hours following the therapeutic agent.

In another embodiment, the present invention provides a method oftreating an inflammatory disease, disorder or condition by administeringto a patient in need thereof a provided compound or a pharmaceuticallyacceptable salt thereof and one or more additional therapeutic agents.Such additional therapeutic agents may be small molecules or recombinantbiologic agents and include, for example, acetaminophen, non-steroidalanti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen,etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroidssuch as prednisone, prednisolone, methylprednisolone, hydrocortisone,and the like, probenecid, allopurinol, febuxostat (Uloric®),sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine(Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), goldsalts such as gold thioglucose (Solganal®), gold thiomalate(Myochrysine®) and auranofin (Ridaura®), D-penicillamine (Depen® orCuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®),chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide(Arava®) and “anti-TNF” agents such as etanercept (Enbrel®), infliximab(Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®) andadalimumab (Humira®), “anti-IL-1” agents such as anakinra (Kineret®) andrilonacept (Arcalyst®), canakinumab (Ilaris®), anti-Jak inhibitors suchas tofacitinib, antibodies such as rituximab (Rituxan®), “anti-T-cell”agents such as abatacept (Orencia®), “anti-IL-6” agents such astocilizumab (Actemra®), diclofenac, cortisone, hyaluronic acid (Synvisc®or Hyalgan®), monoclonal antibodies such as tanezumab, anticoagulantssuch as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®),antidiarrheals such as diphenoxylate (Lomotil®) and loperamide(Imodium®), bile acid binding agents such as cholestyramine, alosetron(Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk ofMagnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® andSenokot®, anticholinergics or antispasmodics such as dicyclomine(Bentyl®), Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA,Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®),pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®),salmeterol xinafoate (Serevent®) and formoterol (Foradil®),anticholinergic agents such as ipratropium bromide (Atrovent®) andtiotropium (Spiriva®), inhaled corticosteroids such as beclomethasonedipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide(Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), andflunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, cromolyn sodium(Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®,Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, IgE antibodies such asomalizumab (Xolair®), nucleoside reverse transcriptase inhibitors suchas zidovudine (Retrovir®), abacavir (Ziagen®), abacavir/lamivudine(Epzicom®), abacavir/lamivudine/zidovudine (Trizivir®), didanosine(Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®),lamivudine/zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine(Hivid®), non-nucleoside reverse transcriptase inhibitors such asdelavirdine (Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®)and etravirine (Intelence®), nucleotide reverse transcriptase inhibitorssuch as tenofovir (Viread®), protease inhibitors such as amprenavir(Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®),fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir(Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir(Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitorssuch as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integraseinhibitors such as raltegravir (Isentress®), doxorubicin(Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®), anddexamethasone (Decadron®) in combination with lenalidomide (Revlimid®),or any combination(s) thereof.

In another embodiment, the present invention provides a method oftreating gout comprising administering to a patient in need thereof aprovided compound or a pharmaceutically acceptable salt thereof and oneor more additional therapeutic agents selected from non-steroidalanti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen,etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroidssuch as prednisone, prednisolone, methylprednisolone, hydrocortisone,and the like, probenecid, allopurinol and febuxostat (Uloric®).

In another embodiment, the present invention provides a method oftreating rheumatoid arthritis comprising administering to a patient inneed thereof a provided compound or a pharmaceutically acceptable saltthereof and one or more additional therapeutic agents selected fromnon-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin,ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroidssuch as prednisone, prednisolone, methylprednisolone, hydrocortisone,and the like, sulfasalazine (Azulfidine®), antimalarials such ashydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate(Rheumatrex®), gold salts such as gold thioglucose (Solganal®), goldthiomalate (Myochrysine®) and auranofin (Ridaura®), D-penicillamine(Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide(Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®),leflunomide (Arava®) and “anti-TNF” agents such as etanercept (Enbrel®),infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol(Cimzia®) and adalimumab (Humira®), “anti-IL-1” agents such as anakinra(Kineret®) and rilonacept (Arcalyst®), antibodies such as rituximab(Rituxan®), “anti-T-cell”agents such as abatacept (Orencia®) and“anti-IL-6” agents such as tocilizumab (Actemra®).

In some embodiments, the present invention provides a method of treatingosteoarthritis comprising administering to a patient in need thereof aprovided compound or a pharmaceutically acceptable salt thereof and oneor more additional therapeutic agents selected from acetaminophen,non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin,ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, diclofenac,cortisone, hyaluronic acid (Synvisc® or Hyalgan®) and monoclonalantibodies such as tanezumab.

In some embodiments, the present invention provides a method of treatinglupus comprising administering to a patient in need thereof a providedcompound or a pharmaceutically acceptable salt thereof and one or moreadditional therapeutic agents selected from acetaminophen, non-steroidalanti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen,etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone,prednisolone, methylprednisolone, hydrocortisone, and the like,antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine(Aralen®), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®),azathioprine (Imuran®) and anticoagulants such as heparin (Calcinparine®or Liquaemin®) and warfarin (Coumadin®).

In some embodiments, the present invention provides a method of treatinginflammatory bowel disease comprising administering to a patient in needthereof a provided compound or a pharmaceutically acceptable saltthereof and one or more additional therapeutic agents selected frommesalamine (Asacol®) sulfasalazine (Azulfidine®), antidiarrheals such asdiphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid bindingagents such as cholestyramine, alosetron (Lotronex®), lubiprostone(Amitiza®), laxatives such as Milk of Magnesia, polyethylene glycol(MiraLax®), Dulcolax®, Correctol® and Senokot® and anticholinergics orantispasmodics such as dicyclomine (Bentyl®), anti-TNF therapies,steroids, and antibiotics such as Flagyl or ciprofloxacin.

In some embodiments, the present invention provides a method of treatingasthma comprising administering to a patient in need thereof a providedcompound or a pharmaceutically acceptable salt thereof and one or moreadditional therapeutic agents selected from anti-IL-33 antibodies suchas REGN3500 (SAR440340) or CNTO 7160, Singulair®, beta-2 agonists suchas albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®),metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutalinesulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol(Foradil®), anticholinergic agents such as ipratropium bromide(Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such asprednisone, prednisolone, beclomethasone dipropionate (Beclovent®,Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone(Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), AfViar®,Symbicort®, and Dulera®, cromolyn sodium (Intal®), methylxanthines suchas theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) andaminophylline, and IgE antibodies such as omalizumab (Xolair®).

In some embodiments, the present invention provides a method of treatingCOPD comprising administering to a patient in need thereof a providedcompound or a pharmaceutically acceptable salt thereof and one or moreadditional therapeutic agents selected from beta-2 agonists such asalbuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®),metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutalinesulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol(Foradil®), anticholinergic agents such as ipratropium bromide(Atrovent®) and tiotropium (Spiriva®), methylxanthines such astheophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) andaminophylline, inhaled corticosteroids such as prednisone, prednisolone,beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®),triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide(Pulmocort®), flunisolide (Aerobid®), AfViar®, Symbicort®, and Dulera®,In some embodiments, the present invention provides a method of treatingeosinophilic COPD comprising administering to a patient in need thereofa provided compound or a pharmaceutically acceptable salt thereof andone or more additional therapeutic agents selected from an anti-IF-33antibody such as REGN3500 (SAR440340) or CNTO 7160. In some embodiments,the present invention provides amethod of treating eosinophilic asthmacomprising administering to a patient in need thereof a providedcompound or a pharmaceutically acceptable salt thereof and one or moreadditional therapeutic agents selected from an anti-IF-33 antibody suchas REGN3500 (SAR440340) or CNTO 7160.

In some embodiments, the present invention provides a method of treatingHIV comprising administering to a patient in need thereof a providedcompound or a pharmaceutically acceptable salt thereof and one or moreadditional therapeutic agents selected from nucleoside reversetranscriptase inhibitors such as zidovudine (Retrovir®), abacavir(Ziagen®), abacavir/lamivudine (Epzicom®),abacavir/lamivudine/zidovudine (Trizivir®), didanosine (Videx®),emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine/zidovudine(Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®),non-nucleoside reverse transcriptase inhibitors such as delavirdine(Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®) andetravirine (Intelence®), nucleotide reverse transcriptase inhibitorssuch as tenofovir (Viread®), protease inhibitors such as amprenavir(Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®),fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir(Kaletra®), nelfmavir (Viracept®), ritonavir (Norvir®), saquinavir(Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitorssuch as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integraseinhibitors such as raltegravir (Isentress®), and combinations thereof.

In another embodiment, the present invention provides a method oftreating a hematological malignancy comprising administering to apatient in need thereof a provided compound or a pharmaceuticallyacceptable salt thereof and one or more additional therapeutic agentsselected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®),doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, ahedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor,a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinationsthereof.

In another embodiment, the present invention provides a method oftreating a solid tumor comprising administering to a patient in needthereof a provided compound or a pharmaceutically acceptable saltthereof and one or more additional therapeutic agents selected fromrituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin(Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehogsignaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

In another embodiment, the present invention provides a method oftreating a hematological malignancy comprising administering to apatient in need thereof a provided compound or a pharmaceuticallyacceptable salt thereof and a Hedgehog (Hh) signaling pathway inhibitor.In some embodiments, the hematological malignancy is DLBCL (Ramirez etal “Defining causative factors contributing in the activation ofhedgehog signaling in diffuse large B-cell lymphoma” Leuk. Res. (2012),published online July 17, and incorporated herein by reference in itsentirety).

In another embodiment, the present invention provides a method oftreating diffuse large B-cell lymphoma (DLBCL) comprising administeringto a patient in need thereof a provided compound or a pharmaceuticallyacceptable salt thereof and one or more additional therapeutic agentsselected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®),doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, ahedgehog signaling inhibitor, and combinations thereof.

In some embodiments, the present invention provides a method of treatingDLBCL comprising administering to a patient in need thereof a providedcompound or a pharmaceutically acceptable salt thereof and a CHOP(cyclophosphamide, Hydrodaunorubicin®, Oncovin®, and prednisone orprednisolone) or R-CHOP (rituximab, cyclophosphamide,Hydrodaunorubicin®, Oncovin®, and prednisone or prednisolone)chemotherapy regimen.

In some embodiments, the present invention provides a method of treatingDLBCL comprising administering to a patient in need thereof a providedcompound or a pharmaceutically acceptable salt thereof and arituximab/bendamustine chemotherapy regimen.

In some embodiments, the present invention provides a method of treatingDLBCL comprising administering to a patient in need thereof a providedcompound or a pharmaceutically acceptable salt thereof and a BTKinhibitor (e.g., ibrutinib).

In some embodiments, the present invention provides a method of treatingDLBCL comprising administering to a patient in need thereof a providedcompound or a pharmaceutically acceptable salt thereof and an anti-CD20antibody (e.g., rituximab).

In some embodiments, the present invention provides a method of treatingDLBCL comprising administering to a patient in need thereof a providedcompound or a pharmaceutically acceptable salt thereof and an anti-CD79BADC (e.g., polatuzumab).

In some embodiments, the present invention provides a method of treatingDLBCL comprising administering to a patient in need thereof a providedcompound or a pharmaceutically acceptable salt thereof and a BCL2inhibitor (e.g., venetoclax).

In some embodiments, the present invention provides a method of treatingDLBCL comprising administering to a patient in need thereof a providedcompound or a pharmaceutically acceptable salt thereof and lenalidomideor pomalidomide

In some embodiments, the present invention provides a method of treatingDLBCL comprising administering to a patient in need thereof a providedcompound or a pharmaceutically acceptable salt thereof and a PI3Kinhibitor (e.g., umbralisib).

In some embodiments, the present invention provides a method of treatinga T-cell disease or deficiency describing herein comprisingadministering to a patient in need thereof a provided compound or apharmaceutically acceptable salt thereof and a PI3K inhibitor (e.g.,umbralisib).

In some embodiments, the present invention provides a method of treatingDLBCL comprising administering to a patient in need thereof a providedcompound or a pharmaceutically acceptable salt thereof and a protesomeinhibitor (e.g., bortezomib)

In some embodiments, the present invention provides a method of treatinga T-cell disease or deficiency describing herein comprisingadministering to a patient in need thereof a provided compound or apharmaceutically acceptable salt thereof and a protesome inhibitor(e.g., bortezomib).

In another embodiment, the present invention provides a method oftreating multiple myeloma comprising administering to a patient in needthereof a provided compound or a pharmaceutically acceptable saltthereof and one or more additional therapeutic agents selected frombortezomib (Velcade®), and dexamethasone (Decadron®), a hedgehogsignaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2inhibitor, a PI3K inhibitor, a SYK inhibitor in combination withlenalidomide (Revlimid®).

In another embodiment, the present invention provides a method oftreating Waldenström's macroglobulinemia comprising administering to apatient in need thereof a provided compound or a pharmaceuticallyacceptable salt thereof and one or more additional therapeutic agentsselected from chlorambucil (Leukeran®), cyclophosphamide (Cytoxan®,Neosar®), fludarabine (Fludara®), cladribine (Leustatin®), rituximab(Rituxan®), a hedgehog signaling inhibitor, a BTK inhibitor, aJAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, and a SYKinhibitor.

In some embodiments, one or more other therapeutic agent is anantagonist of the hedgehog pathway. Approved hedgehog pathway inhibitorswhich may be used in the present invention include sonidegib (Odomzo®,Sun Pharmaceuticals); and vismodegib (Erivedge®, Genentech), both fortreatment of basal cell carcinoma.

In some embodiments, one or more other therapeutic agent is a Poly ADPribose polymerase (PARP) inhibitor. In some embodiments, a PARPinhibitor is selected from olaparib (Lynparza®, AstraZeneca); rucaparib(Rubraca®, Clovis Oncology); niraparib (Zejula®, Tesaro); talazoparib(MDV3800/BMN 673/LT00673, Medivation/Pfizer/Biomarin); veliparib(ABT-888, Abb Vie); and BGB-290 (BeiGene, Inc.).

In some embodiments, one or more other therapeutic agent is a histonedeacetylase (HDAC) inhibitor. In some embodiments, an HDAC inhibitor isselected from vorinostat (Zolinza®, Merck); romidepsin (Istodax®,Celgene); panobinostat (Farydak®, Novartis); belinostat (Beleodaq®,Spectrum Pharmaceuticals); entinostat (SNDX-275, Syndax Pharmaceuticals)(NCT00866333); and chidamide (Epidaza®, HBI-8000, ChipscreenBiosciences, China).

In some embodiments, one or more other therapeutic agent is a CDKinhibitor, such as a CDK4/CDK6 inhibitor. In some embodiments, a CDK 4/6inhibitor is selected from palbociclib (Ibrance®, Pfizer); ribociclib(Kisqali®, Novartis); abemaciclib (Ly2835219, Eli Lilly); andtrilaciclib (G1T28, G1 Therapeutics).

In some embodiments, one or more other therapeutic agent is a folic acidinhibitor. Approved folic acid inhibitors useful in the presentinvention include pemetrexed (Alimta®, Eli Lilly).

In some embodiments, one or more other therapeutic agent is a CCchemokine receptor 4 (CCR4) inhibitor. CCR4 inhibitors being studiedthat may be useful in the present invention include mogamulizumab(Poteligeo®, KyowaHakko Kirin, Japan).

In some embodiments, one or more other therapeutic agent is anisocitrate dehydrogenase (IDH) inhibitor. IDH inhibitors being studiedwhich may be used in the present invention include AG120 (Celgene;NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032(Bayer, NCT02746081); IDH305 (Novartis, NCT02987010).

In some embodiments, one or more other therapeutic agent is an arginaseinhibitor. Arginase inhibitors being studied which may be used in thepresent invention include AEB1102 (pegylated recombinant arginase,Aeglea Biotherapeutics), which is being studied in Phase 1 clinicaltrials for acute myeloid leukemia and myelodysplastic syndrome(NCT02732184) and solid tumors (NCT02561234); and CB-1158 (CalitheraBiosciences).

In some embodiments, one or more other therapeutic agent is aglutaminase inhibitor. Glutaminase inhibitors being studied which may beused in the present invention include CB-839 (Calithera Biosciences).

In some embodiments, one or more other therapeutic agent is an antibodythat binds to tumor antigens, that is, proteins expressed on the cellsurface of tumor cells. Approved antibodies that bind to tumor antigenswhich may be used in the present invention include rituximab (Rituxan®,Genentech/Biogenldec); ofatumumab (anti-CD20, Arzerra®,GlaxoSmithKline); obinutuzumab (anti-CD20, Gazyva®, Genentech),ibritumomab (anti-CD20 and Yttrium-90, Zevalin®, SpectrumPharmaceuticals); daratumumab (anti-CD38, Darzalex®, Janssen Biotech),dinutuximab (anti-glycolipid GD2, Unituxin®, United Therapeutics);trastuzumab (anti-HER2, Herceptin®, Genentech); ado-trastuzumabemtansine (anti-HER2, fused to emtansine, Kadcyla®, Genentech); andpertuzumab (anti-HER2, Peseta®, Genentech); and brentuximab vedotin(anti-CD30-drug conjugate, Adcetris®, Seattle Genetics).

In some embodiments, one or more other therapeutic agent is atopoisomerase inhibitor. Approved topoisomerase inhibitors useful in thepresent invention include irinotecan (Onivyde®, MerrimackPharmaceuticals); topotecan (Hycamtin®, GlaxoSmithKline). Topoisomeraseinhibitors being studied which may be used in the present inventioninclude pixantrone (Pixuvri®, CTI Biopharma).

In some embodiments, one or more other therapeutic agent is an inhibitorof anti-apoptotic proteins, such as BCL-2. Approved anti-apoptoticswhich may be used in the present invention include venetoclax(Venclexta®, AbbVie/Genentech); and blinatumomab (Blincyto®, Amgen).Other therapeutic agents targeting apoptotic proteins which haveundergone clinical testing and may be used in the present inventioninclude navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).

In some embodiments, one or more other therapeutic agent is an androgenreceptor inhibitor. Approved androgen receptor inhibitors useful in thepresent invention include enzalutamide (Xtandi®, Astellas/Medivation);approved inhibitors of androgen synthesis include abiraterone (Zytiga®,Centocor/Ortho); approved antagonist of gonadotropin-releasing hormone(GnRH) receptor (degaralix, Firmagon®, Ferring Pharmaceuticals).

In some embodiments, one or more other therapeutic agent is a selectiveestrogen receptor modulator (SERM), which interferes with the synthesisor activity of estrogens. Approved SERMs useful in the present inventioninclude raloxifene (Evista®, Eli Lilly).

In some embodiments, one or more other therapeutic agent is an inhibitorof bone resorption. An approved therapeutic which inhibits boneresorption is Denosumab (Xgeva®, Amgen), an antibody that binds toRANKL, prevents binding to its receptor RANK, found on the surface ofosteoclasts, their precursors, and osteoclast-like giant cells, whichmediates bone pathology in solid tumors with osseous metastases. Otherapproved therapeutics that inhibit bone resorption includebisphosphonates, such as zoledronic acid (Zometa®, Novartis).

In some embodiments, one or more other therapeutic agent is an inhibitorof interaction between the two primary p53 suppressor proteins, MDMX andMDM2. Inhibitors of p53 suppression proteins being studied which may beused in the present invention include ALRN-6924 (Aileron), a stapledpeptide that equipotently binds to and disrupts the interaction of MDMXand MDM2 with p53. ALRN-6924 is currently being evaluated in clinicaltrials for the treatment of AML, advanced myelodysplastic syndrome (MDS)and peripheral T-cell lymphoma (PTCL) (NCT02909972; NCT02264613).

In some embodiments, one or more other therapeutic agent is an inhibitorof transforming growth factor-beta (TGF-beta or TGFβ). Inhibitors ofTGF-beta proteins being studied which may be used in the presentinvention include NIS793 (Novartis), an anti-TGF-beta antibody beingtested in the clinic for treatment of various cancers, including breast,lung, hepatocellular, colorectal, pancreatic, prostate and renal cancer(NCT 02947165). In some embodiments, the inhibitor of TGF-beta proteinsis fresolimumab (GC1008; Sanofi-Genzyme), which is being studied formelanoma (NCT00923169); renal cell carcinoma (NCT00356460); andnon-small cell lung cancer (NCT02581787). Additionally, in someembodiments, the additional therapeutic agent is a TGF-beta trap, suchas described in Connolly et al. (2012) Int'l J. Biological Sciences8:964-978. One therapeutic compound currently in clinical trials fortreatment of solid tumors is M7824 (Merck KgaA—formerly MSB0011459X),which is a bispecific, anti-PD-L1/TGFβ trap compound (NCT02699515); and(NCT02517398). M7824 is comprised of a fully human IgG1 antibody againstPD-L1 fused to the extracellular domain of human TGF-beta receptor II,which functions as a TGFβ “trap.”

In some embodiments, one or more other therapeutic agent is selectedfrom glembatumumab vedotin-monomethyl auristatin E (MMAE) (Celldex), ananti-glycoprotein NMB (gpNMB) antibody (CR011) linked to the cytotoxicMMAE. gpNMB is a protein overexpressed by multiple tumor typesassociated with cancer cells' ability to metastasize.

In some embodiments, one or more other therapeutic agent is anantiproliferative compound. Such antiproliferative compounds include,but are not limited to aromatase inhibitors; antiestrogens;topoisomerase I inhibitors; topoisomerase II inhibitors; microtubuleactive compounds; alkylating compounds; histone deacetylase inhibitors;compounds which induce cell differentiation processes; cyclooxygenaseinhibitors; MMP inhibitors; mTOR inhibitors; antineoplasticantimetabolites; platin compounds; compounds targeting/decreasing aprotein or lipid kinase activity and further anti-angiogenic compounds;compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase; gonadorelin agonists; anti-androgens; methionineaminopeptidase inhibitors; matrix metalloproteinase inhibitors;bisphosphonates; biological response modifiers; antiproliferativeantibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms;telomerase inhibitors; proteasome inhibitors; compounds used in thetreatment of hematologic malignancies; compounds which target, decreaseor inhibit the activity of Flt-3; Hsp90 inhibitors such as 17-AAG(17-allylaminogeldanamycin, NSC330507), 17-DMAG(17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545),IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics;temozolomide (Temodal®); kinesin spindle protein inhibitors, such asSB715992 or SB743921 from GlaxoSmithKline, or pentamidine/chlorpromazinefrom CombinatoRx; MEK inhibitors such as ARRY142886 from ArrayBioPharma, AZd₆244 from AstraZeneca, PD 181461 from Pfizer andleucovorin.

In some embodiments, the present invention provides a method of treatingAlzheimer's disease comprising administering to a patient in needthereof a provided compound or a pharmaceutically acceptable saltthereof and one or more additional therapeutic agents selected fromdonepezil (Aricept®), rivastigmine (Excelon®), galantamine (Razadyne®),tacrine (Cognex®), and memantine (Namenda®).

In some embodiments, one or more other therapeutic agent is a taxanecompound, which causes disruption of microtubules, which are essentialfor cell division. In some embodiments, a taxane compound is selectedfrom paclitaxel (Taxol®, Bristol-Myers Squibb), docetaxel (Taxotere®,Sanofi-Aventis; Docefrez®, Sun Pharmaceutical), albumin-bound paclitaxel(Abraxane®; Abraxis/Celgene), cabazitaxel (Jevtana®, Sanofi-Aventis),and SID530 (SK Chemicals, Co.) (NCT00931008).

In some embodiments, one or more other therapeutic agent is a nucleosideinhibitor, or a therapeutic agent that interferes with normal DNAsynthesis, protein synthesis, cell replication, or will otherwiseinhibit rapidly proliferating cells.

In some embodiments, a nucleoside inhibitor is selected from trabectedin(guanidine alkylating agent, Yondelis®, Janssen Oncology),mechlorethamine (alkylating agent, Valchlor®, Aktelion Pharmaceuticals);vincristine (Oncovin®, Eh Lilly; Vincasar®, Teva Pharmaceuticals;Marqibo®, Talon Therapeutics); temozolomide (prodrug to alkylating agent5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC) Temodar®,Merck); cytarabine injection (ara-C, antimetabolic cytidine analog,Pfizer); lomustine (alkylating agent, CeeNU®, Bristol-Myers Squibb;Gleostine®, NextSource Biotechnology); azacitidine (pyrimidinenucleoside analog of cytidine, Vidaza®, Celgene); omacetaxinemepesuccinate (cephalotaxine ester) (protein synthesis inhibitor,Synribo®; Teva Pharmaceuticals); asparaginase Erwinia chrysanthemi(enzyme for depletion of asparagine, Elspar®, Lundbeck; Erwinaze®, EUSAPharma); eribulin mesylate (microtubule inhibitor, tubulin-basedantimitotic, Halaven®, Eisai); cabazitaxel (microtubule inhibitor,tubulin-based antimitotic, Jevtana®, Sanofi-Aventis); capacetrine(thymidylate synthase inhibitor, Xeloda®, Genentech); bendamustine(bifimctional mechlorethamine derivative, believed to form interstrandDNA cross-links, Treanda®, Cephalon/Teva); ixabepilone (semi-syntheticanalog of epothilone B, microtubule inhibitor, tubulin-basedantimitotic, Ixempra®, Bristol-Myers Squibb); nelarabine (prodrug ofdeoxyguanosine analog, nucleoside metabolic inhibitor, Arranon®,Novartis); clorafabine (prodrug of ribonucleotide reductase inhibitor,competitive inhibitor of deoxycytidine, Clolar®, Sanofi-Aventis); andtrifluridine and tipiracil (thymidine-based nucleoside analog andthymidine phosphorylase inhibitor, Lonsurf®, Taiho Oncology).

In some embodiments, one or more other therapeutic agent is a kinaseinhibitor or VEGF-R antagonist. Approved VEGF inhibitors and kinaseinhibitors useful in the present invention include: bevacizumab(Avastin®, Genentech/Roche) an anti-VEGF monoclonal antibody;ramucirumab (Cyramza®, Eli Lilly), an anti-VEGFR-2 antibody andziv-aflibercept, also known as VEGF Trap (Zaltrap®; Regeneron/Sanofi).VEGFR inhibitors, such as regorafenib (Stivarga®, Bayer); vandetanib(Caprelsa®, AstraZeneca); axitinib (Inlyta®, Pfizer); and lenvatinib(Lenvima®, Eisai); Raf inhibitors, such as sorafenib (Nexavar®, Bayer AGand Onyx); dabrafenib (Tafinlar®, Novartis); and vemurafenib (Zelboraf®,Genentech/Roche); MEK inhibitors, such as cobimetanib (Cotellic®,Exelexis/Genentech/Roche); trametinib (Mekinist®, Novartis); Bcr-Abltyrosine kinase inhibitors, such as imatinib (Gleevec®, Novartis);nilotinib (Tasigna®, Novartis); dasatinib (Sprycel®,BristolMyersSquibb); bosutinib (Bosulif®, Pfizer); and ponatinib(Inclusig®, Ariad Pharmaceuticals); Her2 and EGFR inhibitors, such asgefitinib (Iressa®, AstraZeneca); erlotinib (Tarceeva®,Genentech/Roche/Astellas); lapatinib (Tykerb®, Novartis); afatinib(Gilotrif®, Boehringer Ingelheim); osimertinib (targeting activatedEGFR, Tagrisso®, AstraZeneca); and brigatinib (Alunbrig®, AriadPharmaceuticals); c-Met and VEGFR2 inhibitors, such as cabozanitib(Cometriq®, Exelexis); and multikinase inhibitors, such as sunitinib(Sutent®, Pfizer); pazopanib (Votrient®, Novartis); ALK inhibitors, suchas crizotinib (Xalkori®, Pfizer); ceritinib (Zykadia®, Novartis); andalectinib (Alecenza®, Genentech/Roche); Bruton's tyrosine kinaseinhibitors, such as ibrutinib (Imbruvica®, Pharmacyclics/Janssen); andFlt3 receptor inhibitors, such as midostaurin (Rydapt®, Novartis).

Other kinase inhibitors and VEGF-R antagonists that are in developmentand may be used in the present invention include tivozanib (AveoPharmaceuticals); vatalanib (Bayer/Novartis); lucitanib (ClovisOncology); dovitinib (TKI258, Novartis); Chiauanib (ChipscreenBiosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories);neratinib (HKI-272, Puma Biotechnology); radotinib (Supect®, IY5511,Il-Yang Pharmaceuticals, S. Korea); ruxolitinib (Jakafi®, IncyteCorporation); PTC299 (PTC Therapeutics); CP-547,632 (Pfizer); foretinib(Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo) and motesanib(Amgen/Takeda).

In another embodiment, the present invention provides a method oftreating organ transplant rejection or graft vs. host disease comprisingadministering to a patient in need thereof a provided compound or apharmaceutically acceptable salt thereof and one or more additionaltherapeutic agents selected from a steroid, cyclosporin, FK506,rapamycin, a hedgehog signaling inhibitor, a BTK inhibitor, aJAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, and a SYKinhibitor.

In another embodiment, the present invention provides a method oftreating or lessening the severity of a disease comprising administeringto a patient in need thereof a provided compound or a pharmaceuticallyacceptable salt thereof and a BTK inhibitor, wherein the disease isselected from inflammatory bowel disease, arthritis, systemic lupuserythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura(ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis,Still's disease, juvenile arthritis, diabetes, myasthenia gravis,Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, autoimmunethyroiditis, Sjogren's syndrome, multiple sclerosis, systemic sclerosis,Lyme neuroborreliosis, Guillain-Barre syndrome, acute disseminatedencephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome,ankylosing spondylosis, antiphospholipid antibody syndrome, aplasticanemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia,celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenicpurpura, optic neuritis, scleroderma, primary biliary cirrhosis,Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warmautoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis,alopecia universalis, Behcet's disease, chronic fatigue, dysautonomia,membranous glomerulonephropathy, endometriosis, interstitial cystitis,pemphigus vulgaris, bullous pemphigoid, neuromyotonia, scleroderma,vulvodynia, a hyperproliferative disease, rejection of transplantedorgans or tissues, Acquired Immunodeficiency Syndrome (AIDS, also knownas HIV), type 1 diabetes, graft versus host disease, transplantation,transfusion, anaphylaxis, allergies (e.g., allergies to plant pollens,latex, drugs, foods, insect poisons, animal hair, animal dander, dustmites, or cockroach calyx), type I hypersensitivity, allergicconjunctivitis, allergic rhinitis, and atopic dermatitis, asthma,appendicitis, atopic dermatitis, asthma, allergy, blepharitis,bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis,cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn'sdisease, cystitis, dacryoadenitis, dermatitis, dermatomyositis,encephalitis, endocarditis, endometritis, enteritis, enterocolitis,epicondylitis, epididymitis, fasciitis, fibrositis, gastritis,gastroenteritis, Henoch-Schonlein purpura, hepatitis, hidradenitissuppurativa, immunoglobulin A nephropathy, interstitial lung disease,laryngitis, mastitis, meningitis, myelitis myocarditis, myositis,nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis,parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis,pneumonitis, pneumonia, polymyositis, proctitis, prostatitis,pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis,tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis,vasculitis, or vulvitis, B-cell proliferative disorder, e.g., diffuselarge B cell lymphoma, follicular lymphoma, chronic lymphocyticlymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia,B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenstrommacroglobulinemia, splenic marginal zone lymphoma, multiple myeloma(also known as plasma cell myeloma), non-Hodgkin's lymphoma, Hodgkin'slymphoma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodalmarginal zone B cell lymphoma, mantle cell lymphoma, mediastinal(thymic) large B cell lymphoma, intravascular large B cell lymphoma,primary effusion lymphoma, Burkitt lymphoma/leukemia, or lymphomatoidgranulomatosis, breast cancer, prostate cancer, or cancer of the mastcells (e.g., mastocytoma, mast cell leukemia, mast cell sarcoma,systemic mastocytosis), bone cancer, colorectal cancer, pancreaticcancer, diseases of the bone and joints including, without limitation,rheumatoid arthritis, seronegative spondyloarthropathies (includingankylosing spondylitis, psoriatic arthritis and Reiter's disease),Behcet's disease, Sjogren's syndrome, systemic sclerosis, osteoporosis,bone cancer, bone metastasis, a thromboembolic disorder, (e.g.,myocardial infarct, angina pectoris, reocclusion after angioplasty,restenosis after angioplasty, reocclusion after aortocoronary bypass,restenosis after aortocoronary bypass, stroke, transitory ischemia, aperipheral arterial occlusive disorder, pulmonary embolism, deep venousthrombosis), inflammatory pelvic disease, urethritis, skin sunburn,sinusitis, pneumonitis, encephalitis, meningitis, myocarditis,nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis,dermatitis, gingivitis, appendicitis, pancreatitis, cholocystitus,agammaglobulinemia, psoriasis, allergy, Crohn's disease, irritable bowelsyndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection,hyperacute rejection of transplanted organs, asthma, allergic rhinitis,chronic obstructive pulmonary disease (COPD), autoimmune polyglandulardisease (also known as autoimmune polyglandular syndrome), autoimmunealopecia, pernicious anemia, glomerulonephritis, dermatomyositis,multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic andthrombocytopenic states, Goodpasture's syndrome, atherosclerosis,Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes,septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis,psoriatic arthritis, juvenile arthritis, osteoarthritis, chronicidiopathic thrombocytopenic purpura, Waldenstrom macroglobulinemia,myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis,degenerative joint disease, vitiligo, autoimmune hypopituitarism,Guillain-Barre syndrome, Behcet's disease, scleraderma, mycosisfungoides, acute inflammatory responses (such as acute respiratorydistress syndrome and ischemia/reperfusion injury), and Graves' disease.

In another embodiment, the present invention provides a method oftreating or lessening the severity of a disease comprising administeringto a patient in need thereof a provided compound or a pharmaceuticallyacceptable salt thereof and a PI3K inhibitor, wherein the disease isselected from a cancer, a neurodegenative disorder, an angiogenicdisorder, a viral disease, an autoimmune disease, an inflammatorydisorder, a hormone-related disease, conditions associated with organtransplantation, immunodeficiency disorders, a destructive bonedisorder, a proliferative disorder, an infectious disease, a conditionassociated with cell death, thrombin-induced platelet aggregation,chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL),liver disease, pathologic immune conditions involving T cell activation,a cardiovascular disorder, and a CNS disorder.

In another embodiment, the present invention provides a method oftreating or lessening the severity of a disease comprising administeringto a patient in need thereof a provided compound or a pharmaceuticallyacceptable salt thereof and a PI3K inhibitor, wherein the disease isselected from benign or malignant tumor, carcinoma or solid tumor of thebrain, kidney (e.g., renal cell carcinoma (RCC)), liver, adrenal gland,bladder, breast, stomach, gastric tumors, ovaries, colon, rectum,prostate, pancreas, lung, vagina, endometrium, cervix, testis,genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma,glioblastomas, neuroblastomas, multiple myeloma or gastrointestinalcancer, especially colon carcinoma or colorectal adenoma or a tumor ofthe neck and head, an epidermal hyperproliferation, psoriasis, prostatehyperplasia, a neoplasia, a neoplasia of epithelial character, adenoma,adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cellcarcinoma, non-small-cell lung carcinoma, lymphomas, (including, forexample, non-Hodgkin's Lymphoma (NHL) and Hodgkin's lymphoma (alsotermed Hodgkin's or Hodgkin's disease)), a mammary carcinoma, follicularcarcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma,melanoma, or a leukemia, diseases include Cowden syndrome,Lhermitte-Dudos disease and Bannayan-Zonana syndrome, or diseases inwhich the PI3K/PKB pathway is aberrantly activated, asthma of whatevertype or genesis including both intrinsic (non-allergic) asthma andextrinsic (allergic) asthma, mild asthma, moderate asthma, severeasthma, bronchitic asthma, exercise-induced asthma, occupational asthmaand asthma induced following bacterial infection, acute lung injury(ALI), adult/acute respiratory distress syndrome (ARDS), chronicobstructive pulmonary, airways or lung disease (COPD, COAD or COLD),including chronic bronchitis or dyspnea associated therewith, emphysema,as well as exacerbation of airways hyperreactivity consequent to otherdrug therapy, in particular other inhaled drug therapy, bronchitis ofwhatever type or genesis including, but not limited to, acute,arachidic, catarrhal, croupus, chronic or phthinoid bronchitis,pneumoconiosis (an inflammatory, commonly occupational, disease of thelungs, frequently accompanied by airways obstruction, whether chronic oracute, and occasioned by repeated inhalation of dusts) of whatever typeor genesis, including, for example, aluminosis, anthracosis, asbestosis,chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis,Loffler's syndrome, eosinophilic, pneumonia, parasitic (in particularmetazoan) infestation (including tropical eosinophilia),bronchopulmonary aspergillosis, polyarteritis nodosa (includingChurg-Strauss syndrome), eosinophilic granuloma and eosinophil-relateddisorders affecting the airways occasioned by drug-reaction, psoriasis,contact dermatitis, atopic dermatitis, alopecia areata, erythemamultiforma, dermatitis herpetiformis, scleroderma, vitiligo,hypersensitivity angiitis, urticaria, bullous pemphigoid, lupuserythematosus, pemphisus, epidermolysis bullosa acquisita,conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis,diseases affecting the nose including allergic rhinitis, andinflammatory disease in which autoimmune reactions are implicated orhaving an autoimmune component or etiology, including autoimmunehematological disorders (e.g. hemolytic anemia, aplastic anemia, purered cell anemia and idiopathic thrombocytopenia), systemic lupuserythematosus, rheumatoid arthritis, polychondritis, sclerodoma, Wegenergranulamatosis, dermatomyositis, chronic active hepatitis, myastheniagravis, Steven-Johnson syndrome, idiopathic sprue, autoimmuneinflammatory bowel disease (e.g. ulcerative colitis and Crohn'sdisease), endocrine opthalmopathy, Grave's disease, sarcoidosis,alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis,primary biliary cirrhosis, uveitis (anterior and posterior),keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitiallung fibrosis, psoriatic arthritis and glomerulonephritis (with andwithout nephrotic syndrome, e.g. including idiopathic nephrotic syndromeor minal change nephropathy, restenosis, cardiomegaly, atherosclerosis,myocardial infarction, ischemic stroke and congestive heart failure,Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis,Huntington's disease, and cerebral ischemia, and neurodegenerativedisease caused by traumatic injury, glutamate neurotoxicity and hypoxia.

In some embodiments, one or more other therapeutic agent is aphosphatidylinositol 3 kinase (PI3K) inhibitor. In some embodiments, aPI3K inhibitor is selected from idelalisib (Zydelig®, Gilead), alpelisib(BYL719, Novartis), taselisib (GDC-0032, Genentech/Roche); pictilisib(GDC-0941, Genentech/Roche); copanlisib (BAY806946, Bayer); duvelisib(formerly IPI-145, Infinity Pharmaceuticals); PQR309 (PiqurTherapeutics, Switzerland); and TGR1202 (formerly RP5230, TGTherapeutics).

In some embodiments, the present invention provides a method of treatingAML comprising administering to a patient in need thereof a providedcompound or a pharmaceutically acceptable salt thereof and one or moreadditional therapeutic agents selected from: FLT3 inhibitors; targetedagents such as IDH inhibitors, anti-CD33 ADCs (e.g. Mylotarg), BCL2inhibitors, and Hedgehog inhibitors; and chemotherapy such as AraC,daunarubicin, etoposide, methotrexate, fludarabine, mitozantrone,azacytidine, and corticosteroids.

In some embodiments, the present invention provides a method of treatingMDS comprising administering to a patient in need thereof a providedcompound or a pharmaceutically acceptable salt thereof and one or moreadditional therapeutic agents selected from azacytidine, decitabine andrevlimid.

In some embodiments, the present invention provides a method of treatinginflammatory skin conditions such as hidradenitis suppurativa,comprising administering to a patient in need thereof a providedcompound or a pharmaceutically acceptable salt thereof and one or moreadditional therapeutic agents selected from anti-TNF drugs.

In some embodiments, the present invention provides a method of treatinginflammatory skin conditions such as atopic dermatitis, comprisingadministering to a patient in need thereof a provided compound or apharmaceutically acceptable salt thereof and one or more additionaltherapeutic agents selected from IL-4/IL-13-targeted agents such asdupilumab. In some embodiments, the present invention provides a methodof treating inflammatory skin conditions such as psoriasis, comprisingadministering to a patient in need thereof a provided compound or apharmaceutically acceptable salt thereof and one or more additionaltherapeutic agents selected from anti-IL-17 and anti-IL-23 antibodies.

The compounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of acancer, an autoimmune disorder, a proliferative disorder, aninflammatory disorder, a neurodegenerative or neurological disorder,schizophrenia, a bone-related disorder, liver disease, or a cardiacdisorder. The exact amount required will vary from subject to subject,depending on the species, age, and general condition of the subject, theseverity of the infection, the particular agent, its mode ofadministration, and the like. Compounds of the invention are preferablyformulated in dosage unit form for ease of administration and uniformityof dosage. The expression “dosage unit form” as used herein refers to aphysically discrete unit of agent appropriate for the patient to betreated. It will be understood, however, that the total daily usage ofthe compounds and compositions of the present invention will be decidedby the attending physician within the scope of sound medical judgment.The specific effective dose level for any particular patient or organismwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; the activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts.

Pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracistemally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.R and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

According to one embodiment, the invention relates to a method ofinhibiting protein kinase activity or degrading a protein kinase in abiological sample comprising the step of contacting said biologicalsample with a compound of this invention, or a composition comprisingsaid compound.

According to another embodiment, the invention relates to a method ofinhibiting or degrading IRAK-1, IRAK-2, and/or IRAK-4, or a mutantthereof, activity in a biological sample comprising the step ofcontacting said biological sample with a compound of this invention, ora composition comprising said compound.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Inhibition and/or degradation of a protein kinase, or a protein kinaseselected from IRAK-1, IRAK-2, and/or IRAK-4, or a mutant thereof,activity in a biological sample is useful for a variety of purposes thatare known to one of skill in the art. Examples of such purposes include,but are not limited to, blood transfusion, organ-transplantation,biological specimen storage, and biological assays.

Another embodiment of the present invention relates to a method ofdegrading a protein kinase and/or inhibiting protein kinase activity ina patient comprising the step of administering to said patient acompound of the present invention, or a composition comprising saidcompound.

According to another embodiment, the invention relates to a method ofdegrading and/or inhibiting one or more of IRAK-1, IRAK-2, and/orIRAK-4, or a mutant thereof, activity in a patient comprising the stepof administering to said patient a compound of the present invention, ora composition comprising said compound. In other embodiments, thepresent invention provides a method for treating a disorder mediated byone or more of IRAK-1, IRAK-2, and/or IRAK-4, or a mutant thereof, in apatient in need thereof, comprising the step of administering to saidpatient a compound according to the present invention orpharmaceutically acceptable composition thereof. Such disorders aredescribed in detail herein.

Depending upon the particular condition, or disease, to be treated,additional therapeutic agents that are normally administered to treatthat condition, may also be present in the compositions of thisinvention. As used herein, additional therapeutic agents that arenormally administered to treat a particular disease, or condition, areknown as “appropriate for the disease, or condition, being treated.”

A compound of the current invention may also be used to advantage incombination with other antiproliferative compounds. Suchantiproliferative compounds include, but are not limited to aromataseinhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase IIinhibitors; microtubule active compounds; alkylating compounds; histonedeacetylase inhibitors; compounds which induce cell differentiationprocesses; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors;antineoplastic antimetabolites; platin compounds; compoundstargeting/decreasing a protein or lipid kinase activity and furtheranti-angiogenic compounds; compounds which target, decrease or inhibitthe activity of a protein or lipid phosphatase; gonadorelin agonists;anti-androgens; methionine aminopeptidase inhibitors; matrixmetalloproteinase inhibitors; bisphosphonates; biological responsemodifiers; antiproliferative antibodies; heparanase inhibitors;inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasomeinhibitors; compounds used in the treatment of hematologic malignancies;compounds which target, decrease or inhibit the activity of Flt-3; Hsp90inhibitors such as 17-AAG (17-allylaminogeldanamycin, NSC330507),17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin,NSC707545), IPI-504, CNF1010, CNF2024, CNF 1010 from ConformaTherapeutics; temozolomide (Temodal®); kinesin spindle proteininhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, orpentamidine/chlorpromazine from CombinatoRx; MEK inhibitors such asARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD 181461from Pfizer and leucovorin.

The term “aromatase inhibitor” as used herein relates to a compoundwhich inhibits estrogen production, for instance, the conversion of thesubstrates androstenedione and testosterone to estrone and estradiol,respectively. The term includes, but is not limited to steroids,especially atamestane, exemestane and formestane and, in particular,non-steroids, especially aminoglutethimide, roglethimide,pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole,fadrozole, anastrozole and letrozole. Exemestane is marketed under thetrade name Aromasin™. Formestane is marketed under the trade nameLentaron™. Fadrozole is marketed under the trade name Afema™.Anastrozole is marketed under the trade name Arimidex™. Letrozole ismarketed under the trade names Femara™ or Femar™. Aminoglutethimide ismarketed under the trade name Orimeten™. A combination of the inventioncomprising a chemotherapeutic agent which is an aromatase inhibitor isparticularly useful for the treatment of hormone receptor positivetumors, such as breast tumors.

In some embodiments, one or more other therapeutic agent is an mTORinhibitor, which inhibits cell proliferation, angiogenesis and glucoseuptake. In some embodiments, an mTOR inhibitor is everolimus (Afinitor®,Novartis); temsirolimus (Torisel®, Pfizer); and sirolimus (Rapamune®,Pfizer).

In some embodiments, one or more other therapeutic agent is an aromataseinhibitor. In some embodiments, an aromatase inhibitor is selected fromexemestane (Aromasin®, Pfizer); anastazole (Arimidex®, AstraZeneca) andletrozole (Femara®, Novartis).

The term “antiestrogen” as used herein relates to a compound whichantagonizes the effect of estrogens at the estrogen receptor level. Theterm includes, but is not limited to tamoxifen, fulvestrant, raloxifeneand raloxifene hydrochloride. Tamoxifen is marketed under the trade nameNolvadex™. Raloxifene hydrochloride is marketed under the trade nameEvista™. Fulvestrant can be administered under the trade name Faslodex™.A combination of the invention comprising a chemotherapeutic agent whichis an antiestrogen is particularly useful for the treatment of estrogenreceptor positive tumors, such as breast tumors.

The term “anti-androgen” as used herein relates to any substance whichis capable of inhibiting the biological effects of androgenic hormonesand includes, but is not limited to, bicalutamide (Casodex™). The term“gonadorelin agonist” as used herein includes, but is not limited toabarelix, goserelin and goserelin acetate. Goserelin can be administeredunder the trade name Zoladex™.

The term “topoisomerase I inhibitor” as used herein includes, but is notlimited to topotecan, gimatecan, irinotecan, camptothecian and itsanalogues, 9-nitrocamptothecin and the macromolecular camptothecinconjugate PNU-166148. Irinotecan can be administered, e.g. in the formas it is marketed, e.g. under the trademark Camptosar™. Topotecan ismarketed under the trade name Hycamptin™.

The term “topoisomerase II inhibitor” as used herein includes, but isnot limited to the anthracyclines such as doxorubicin (includingliposomal formulation, such as Caelyx™), daunorubicin, epirubicin,idarubicin and nemorubicin, the anthraquinones mitoxantrone andlosoxantrone, and the podophillotoxines etoposide and teniposide.Etoposide is marketed under the trade name Etopophos™. Teniposide ismarketed under the trade name VM 26-Bristol Doxorubicin is marketedunder the trade name Acriblastin™ or Adriamycin™. Epirubicin is marketedunder the trade name Farmorubicin™. Idarubicin is marketed, under thetrade name Zavedos™. Mitoxantrone is marketed under the trade nameNovantron.

The term “microtubule active agent” relates to microtubule stabilizing,microtubule destabilizing compounds and microtublin polymerizationinhibitors including, but not limited to taxanes, such as paclitaxel anddocetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate,vincristine or vincristine sulfate, and vinorelbine; discodermolides;cochicine and epothilones and derivatives thereof. Paclitaxel ismarketed under the trade name Taxol™. Docetaxel is marketed under thetrade name Taxotere™. Vinblastine sulfate is marketed under the tradename Vinblastin R.P™. Vincristine sulfate is marketed under the tradename Farmistin™.

The term “alkylating agent” as used herein includes, but is not limitedto, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU orGliadel). Cyclophosphamide is marketed under the trade name Cyclostin™.Ifosfamide is marketed under the trade name Holoxan™.

The term “histone deacetylase inhibitors” or “HDAC inhibitors” relatesto compounds which inhibit the histone deacetylase and which possessantiproliferative activity. This includes, but is not limited to,suberoylanilide hydroxamic acid (SAHA).

The term “antineoplastic antimetabolite” includes, but is not limitedto, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylatingcompounds, such as 5-azacytidine and decitabine, methotrexate andedatrexate, and folic acid antagonists such as pemetrexed. Capecitabineis marketed under the trade name Xeloda™. Gemcitabine is marketed underthe trade name Gemzar™.

The term “platin compound” as used herein includes, but is not limitedto, carboplatin, cis -platin, cisplatinum and oxaliplatin. Carboplatincan be administered, e.g., in the form as it is marketed, e.g. under thetrademark Carboplat™. Oxaliplatin can be administered, e.g., in the formas it is marketed, e.g. under the trademark Eloxatin™.

The term “Bcl-2 inhibitor” as used herein includes, but is not limitedto compounds having inhibitory activity against B-cell lymphoma 2protein (Bcl-2), including but not limited to ABT-199, ABT-731, ABT-737,apogossypol, Ascenta's pan-Bcl-2 inhibitors, curcumin (and analogsthereof), dual Bcl-2/Bcl-xL inhibitors (InfinityPharmaceuticals/Novartis Pharmaceuticals), Genasense (G3139), HA14-1(and analogs thereof; see WO 2008/118802, US 2010/0197686), navitoclax(and analogs thereof, see U.S. Pat. No. 7,390,799), NH-1 (ShenayngPharmaceutical University), obatoclax (and analogs thereof, see WO2004/106328, US 2005/0014802), S-001 (Gloria Pharmaceuticals), TW seriescompounds (Univ. of Michigan), and venetoclax. In some embodiments theBcl-2 inhibitor is a small molecule therapeutic. In some embodiments theBcl-2 inhibitor is a peptidomimetic.

The term “compounds targeting/decreasing a protein or lipid kinaseactivity; or a protein or lipid phosphatase activity; or furtheranti-angiogenic compounds” as used herein includes, but is not limitedto, protein tyrosine kinase and/or serine and/or threonine kinaseinhibitors or lipid kinase inhibitors, such as a) compounds targeting,decreasing or inhibiting the activity of the platelet-derived growthfactor-receptors (PDGFR), such as compounds which target, decrease orinhibit the activity of PDGFR, especially compounds which inhibit thePDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, suchas imatinib, SU101, SU6668 and GFB-111; b) compounds targeting,decreasing or inhibiting the activity of the fibroblast growthfactor-receptors (FGFR); c) compounds targeting, decreasing orinhibiting the activity of the insulin-like growth factor receptor I(IGF-IR), such as compounds which target, decrease or inhibit theactivity of IGF-IR, especially compounds which inhibit the kinaseactivity of IGF-I receptor, or antibodies that target the extracellulardomain of IGF-I receptor or its growth factors; d) compounds targeting,decreasing or inhibiting the activity of the Trk receptor tyrosinekinase family, or ephrin B4 inhibitors; e) compounds targeting,decreasing or inhibiting the activity of the Axl receptor tyrosinekinase family; f) compounds targeting, decreasing or inhibiting theactivity of the Ret receptor tyrosine kinase; g) compounds targeting,decreasing or inhibiting the activity of the Kit/SCFR receptor tyrosinekinase, such as imatinib; h) compounds targeting, decreasing orinhibiting the activity of the C-kit receptor tyrosine kinases, whichare part of the PDGFR family, such as compounds which target, decreaseor inhibit the activity of the c-Kit receptor tyrosine kinase family,especially compounds which inhibit the c-Kit receptor, such as imatinib;i) compounds targeting, decreasing or inhibiting the activity of membersof the c-Abl family, their gene-fusion products (e.g. BCR-Abl kinase)and mutants, such as compounds which target decrease or inhibit theactivity of c-Abl family members and their gene fusion products, such asan N-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib(AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; ordasatinib (BMS-354825); j) compounds targeting, decreasing or inhibitingthe activity of members of the protein kinase C (PKC) and Raf family ofserine/threonine kinases, members of the MEK, SRC, JAK/pan-JAK, FAR,PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, TYK2, BTK and TEC family, and/ormembers of the cyclin-dependent kinase family (CDK) includingstaurosporine derivatives, such as midostaurin; examples of furthercompounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1,Perifosine; llmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521;LY333531/LY379196; isochinoline compounds; FTIs; PD184352 or QAN697 (aP13K inhibitor) or AT7519 (CDK inhibitor); k) compounds targeting,decreasing or inhibiting the activity of protein-tyrosine kinaseinhibitors, such as compounds which target, decrease or inhibit theactivity of protein-tyrosine kinase inhibitors include imatinib mesylate(Gleevec™) or tyrphostin such as Tyrphostin A23/RG-50810; AG 99;Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; TyrphostinB44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494;Tyrphostin AG 556, AG957 and adaphostin(4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester;NSC 680410, adaphostin); 1) compounds targeting, decreasing orinhibiting the activity of the epidermal growth factor family ofreceptor tyrosine kinases (EGFRi ErbB2, ErbB3, ErbB4 as homo- orheterodimers) and their mutants, such as compounds which target,decrease or inhibit the activity of the epidermal growth factor receptorfamily are especially compounds, proteins or antibodies which inhibitmembers of the EGF receptor tyrosine kinase family, such as EGFreceptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands,CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin™), cetuximab(Erbitux™), Iressa, Tarceva, OSI-774, C1-1033, EKB-569, GW-2016, E1.1,E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds targeting,decreasing or inhibiting the activity of the c-Met receptor, such ascompounds which target, decrease or inhibit the activity of c-Met,especially compounds which inhibit the kinase activity of c-Metreceptor, or antibodies that target the extracellular domain of c-Met orbind to HGF, n) compounds targeting, decreasing or inhibiting the kinaseactivity of one or more JAK family members (JAK1/JAK2/JAK3/TYK2 and/orpan-JAK), including but not limited to PRT-062070, SB-1578, baricitinib,pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, andruxolitinib; o) compounds targeting, decreasing or inhibiting the kinaseactivity of PI3 kinase (PI3K) including but not limited to ATU-027,SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib,pictrelisib, PF-4691502, BYE-719, dactolisib, XF-147, XF-765, andidelalisib; and; and q) compounds targeting, decreasing or inhibitingthe signaling effects of hedgehog protein (Hh) or smoothened receptor(SMO) pathways, including but not limited to cyclopamine, vismodegib,itraconazole, erismodegib, and IPI-926 (saridegib).

Compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A,or CDC25, such as okadaic acid or a derivative thereof.

In some embodiments, one or more other therapeutic agent is a growthfactor antagonist, such as an antagonist of platelet-derived growthfactor (PDGF), or epidermal growth factor (EGF) or its receptor (EGFR).Approved PDGF antagonists which may be used in the present inventioninclude olaratumab (Lartruvo®; Eh Lilly). Approved EGFR antagonistswhich may be used in the present invention include cetuximab (Erbitux®,Eli Lilly); necitumumab (Portrazza®, Eli Lilly), panitumumab (Vectibix®,Amgen); and osimertinib (targeting activated EGFR, Tagrisso®,AstraZeneca).

The term “PI3K inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against one or more enzymes in thephosphatidylinositol-3-kinase family, including, but not limited toPI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α,p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87.Examples of PI3K inhibitors useful in this invention include but are notlimited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474,buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147,XL-765, and idelalisib.

The term “BTK inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against Bruton's Tyrosine Kinase(BTK), including, but not limited to AVL-292 and ibrutinib.

The term “SYK inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against spleen tyrosine kinase(SYK), including but not limited to PRT-062070, R-343, R-333, Excellair,PRT-062607, and fostamatinib

Further examples of BTK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO 2008/039218, US 2008/0108636 and WO 2011/090760, US2010/0249092, the entirety of each of which is herein incorporated byreference.

Further examples of SYK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO 2003/063794, US 2004/0029902, WO 2005/007623, US2005/0075306, and WO 2006/078846, US 2006/0211657, the entirety of eachof which is herein incorporated by reference.

Further examples of PI3K inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO 2004/019973, US 2004/0106569, WO 2004/089925, US2004/0242631, U.S. Pat. No. 8,138,347, WO 2002/088112, US 2004/0116421,WO 2007/084786, US 2010/0249126, WO 2007/129161, US 2008/0076768, WO2006/122806, US 2008/0194579, WO 2005/113554, US 2008/0275067, and WO2007/044729, US 2010/0087440, the entirety of each of which is hereinincorporated by reference.

Further examples of JAK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO 2009/114512, US 2009/0233903, WO 2008/109943, US2010/0197671, WO 2007/053452, US 2007/0191405, WO 2001/0142246, US2001/0053782, and WO 2007/070514, US 2007/0135461, the entirety of eachof which is herein incorporated by reference.

Further anti-angiogenic compounds include compounds having anothermechanism for their activity, e.g. unrelated to protein or lipid kinaseinhibition e.g. thalidomide (Thalomid™) and TNP-470.

Examples of proteasome inhibitors useful for use in combination withcompounds of the invention include, but are not limited to bortezomib,disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A,carfilzomib, ONX-0912, CEP-18770, and MLN9708.

Compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A,or CDC25, such as okadaic acid or a derivative thereof.

Compounds which induce cell differentiation processes include, but arenot limited to, retinoic acid, α- γ- or δ-tocopherol or α- γ- orδ-tocotrienol.

The term cyclooxygenase inhibitor as used herein includes, but is notlimited to, Cox-2 inhibitors, 5-alkyl substituted2-arylaminophenylacetic acid and derivatives, such as celecoxib(Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib or a 5-alkyl-2-arylaminophenylacetic acid, such as5-methyl-2-(2′-chloro-6′-fluoroanilino)phenyl acetic acid, lumiracoxib.

The term “bisphosphonates” as used herein includes, but is not limitedto, etridonic, clodronic, tiludronic, pamidronic, alendronic,ibandronic, risedronic and zoledronic acid. Etridonic acid is marketedunder the trade name Didronel™. Clodronic acid is marketed under thetrade name Bonefos™. Tiludronic acid is marketed under the trade nameSkelid™. Pamidronic acid is marketed under the trade name Aredia™.Alendronic acid is marketed under the trade name Fosamax™. Ibandronicacid is marketed under the trade name Bondranat™. Risedronic acid ismarketed under the trade name Actonel™. Zoledronic acid is marketedunder the trade name Zometa™. The term “mTOR inhibitors” relates tocompounds which inhibit the mammalian target of rapamycin (mTOR) andwhich possess antiproliferative activity such as sirolimus (Rapamune®),everolimus (Certican™), CCI-779 and ABT578.

The term “heparanase inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit heparin sulfate degradation. The termincludes, but is not limited to, PI-88. The term “biological responsemodifier” as used herein refers to a lymphokine or interferons.

The term “inhibitor of Ras oncogenic isoforms”, such as H-Ras, K-Ras, orN-Ras, as used herein refers to compounds which target, decrease orinhibit the oncogenic activity of Ras; for example, a “farnesyltransferase inhibitor” such as L-744832, DK8G557 or R115777 (Zamestra™).The term “telomerase inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of telomerase. Compounds whichtarget, decrease or inhibit the activity of telomerase are especiallycompounds which inhibit the telomerase receptor, such as telomestatin.

The term “methionine aminopeptidase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of methionineaminopeptidase. Compounds which target, decrease or inhibit the activityof methionine aminopeptidase include, but are not limited to, bengamideor a derivative thereof.

The term “proteasome inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of the proteasome. Compoundswhich target, decrease or inhibit the activity of the proteasomeinclude, but are not limited to, Bortezomib (Velcade™), ); carfilzomib(Kyprolis®, Amgen); and ixazomib (Ninlaro®, Takeda), and MLN 341.

The term “matrix metalloproteinase inhibitor” or (“MMP” inhibitor) asused herein includes, but is not limited to, collagen peptidomimetic andnonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamatepeptidomimetic inhibitor batimastat and its orally bioavailable analoguemarimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551)BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

The term “compounds used in the treatment of hematologic malignancies”as used herein includes, but is not limited to, FMS-like tyrosine kinaseinhibitors, which are compounds targeting, decreasing or inhibiting theactivity of FMS-like tyrosine kinase receptors (Flt-3R); interferon,1-β-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors,which are compounds which target, decrease or inhibit anaplasticlymphoma kinase.

Compounds which target, decrease or inhibit the activity of FMS-liketyrosine kinase receptors (Flt-3R) are especially compounds, proteins orantibodies which inhibit members of the Flt-3R receptor kinase family,such as PKC412, midostaurin, a staurosporine derivative, SU11248 andMLN518.

The term “HSP90 inhibitors” as used herein includes, but is not limitedto, compounds targeting, decreasing or inhibiting the intrinsic ATPaseactivity of HSP90; degrading, targeting, decreasing or inhibiting theHSP90 client proteins via the ubiquitin proteosome pathway. Compoundstargeting, decreasing or inhibiting the intrinsic ATPase activity ofHSP90 are especially compounds, proteins or antibodies which inhibit theATPase activity ofHSP90, such as 17-allylamino,17-demethoxygeldanamycin(17AAG), a geldanamycin derivative; other geldanamycin relatedcompounds; radicicol and HDAC inhibitors.

The term “antiproliferative antibodies” as used herein includes, but isnot limited to, trastuzumab (Herceptin™), Trastuzumab-DMl, erbitux,bevacizumab (Avastin™), rituximab (Rituxan®), PR064553 (anti-CD40) and2C4 Antibody. By antibodies is meant intact monoclonal antibodies,polyclonal antibodies, multispecific antibodies formed from at least 2intact antibodies, and antibodies fragments so long as they exhibit thedesired biological activity.

For the treatment of acute myeloid leukemia (AML), compounds of thecurrent invention can be used in combination with standard leukemiatherapies, especially in combination with therapies used for thetreatment of AML. In particular, compounds of the current invention canbe administered in combination with, for example, farnesyl transferaseinhibitors and/or other drugs useful for the treatment of AML, such asDaunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone,Idarubicin, Carboplatinum and PKC412.

Other anti-leukemic compounds include, for example, Ara-C, a pyrimidineanalog, which is the 2-alpha-hydroxy ribose (arabinoside) derivative ofdeoxycytidine. Also included is the purine analog of hypoxanthine,6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds whichtarget, decrease or inhibit activity of histone deacetylase (HDAC)inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid(SAHA) inhibit the activity of the enzymes known as histonedeacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228(formerly FR901228), Trichostatin A and compounds disclosed in U.S. Pat.No. 6,552,065 including, but not limited to,N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof andN-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof, especially the lactatesalt. Somatostatin receptor antagonists as used herein refer tocompounds which target, treat or inhibit the somatostatin receptor suchas octreotide, and SOM230. Tumor cell damaging approaches refer toapproaches such as ionizing radiation. The term “ionizing radiation”referred to above and hereinafter means ionizing radiation that occursas either electromagnetic rays (such as X-rays and gamma rays) orparticles (such as alpha and beta particles). Ionizing radiation isprovided in, but not limited to, radiation therapy and is known in theart. See Heilman, Principles of Radiation Therapy, Cancer, in Principlesand Practice of Oncology, Devita et al., Eds., 4^(th) Edition, Vol. 1,pp. 248-275 (1993).

Also included are EDG binders and ribonucleotide reductase inhibitors.The term “EDG binders” as used herein refers to a class ofimmunosuppressants that modulates lymphocyte recirculation, such asFTY720. The term “ribonucleotide reductase inhibitors” refers topyrimidine or purine nucleoside analogs including, but not limited to,fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine,5-fluorouracil, cladribine, 6-mercaptopurine (especially in combinationwith ara-C against ALL) and/or pentostatin. Ribonucleotide reductaseinhibitors are especially hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

Also included are in particular those compounds, proteins or monoclonalantibodies of VEGF such as1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceuticallyacceptable salt thereof,l-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate;Angiostatin™; Endostatin™; anthranilic acid amides; ZD4190; ZD6474;SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGFreceptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer such asMacugon; FFT-4 inhibitors, FFT-3 inhibitors, VEGFR-2 IgGI antibody,Angiozyme (RPI 4610) and Bevacizumab (Avastin™).

Photodynamic therapy as used herein refers to therapy which uses certainchemicals known as photosensitizing compounds to treat or preventcancers. Examples of photodynamic therapy include treatment withcompounds, such as Visudyne™ and porfimer sodium.

Angiostatic steroids as used herein refers to compounds which block orinhibit angiogenesis, such as, e.g., anecortave, triamcinolone,hydrocortisone, 11-α-epihydrocotisol, cortexolone,17α-hydroxyprogesterone, corticosterone, desoxycorticosterone,testosterone, estrone and dexamethasone.

Implants containing corticosteroids refers to compounds, such asfluocinolone and dexamethasone.

Other chemotherapeutic compounds include, but are not limited to, plantalkaloids, hormonal compounds and antagonists; biological responsemodifiers, preferably lymphokines or interferons; antisenseoligonucleotides or oligonucleotide derivatives; shRNA or siRNA; ormiscellaneous compounds or compounds with other or unknown mechanism ofaction.

The compounds of the invention are also useful as co-therapeuticcompounds for use in combination with other drug substances such asanti-inflammatory, bronchodilatory or antihistamine drug substances,particularly in the treatment of obstructive or inflammatory airwaysdiseases such as those mentioned hereinbefore, for example aspotentiators of therapeutic activity of such drugs or as a means ofreducing required dosaging or potential side effects of such drugs. Acompound of the invention may be mixed with the other drug substance ina fixed pharmaceutical composition or it may be administered separately,before, simultaneously with or after the other drug substance.Accordingly the invention includes a combination of a compound of theinvention as hereinbefore described with an anti-inflammatory,bronchodilatory, antihistamine or anti-tussive drug substance, saidcompound of the invention and said drug substance being in the same ordifferent pharmaceutical composition.

Suitable anti-inflammatory drugs include steroids, in particularglucocorticosteroids such as budesonide, beclamethasone dipropionate,fluticasone propionate, ciclesonide or mometasone furoate; non-steroidalglucocorticoid receptor agonists; LTB4 antagonists such LY293111,CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247; LTD4antagonists such as montelukast and zafirlukast; PDE4 inhibitors suchcilomilast (Ariflo® GlaxoSmithKline), Roflumilast (Byk Gulden), V-11294A(Napp), BAY19-8004 (Bayer), SCH-351591 (Schering- Plough), Arofylline(Almirall Prodesfarma), PD189659/PD168787 (Parke-Davis), AWD-12-281(Asta Medica), CDC-801 (Celgene), SelCID™ CC-10004 (Celgene),VM554/UM565 (Vemalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo); A2aagonists; A2b antagonists; and beta-2 adrenoceptor agonists such asalbuterol (salbutamol), metaproterenol, terbutaline, salmeterolfenoterol, procaterol, and especially, formoterol and pharmaceuticallyacceptable salts thereof. Suitable bronchodilatory drugs includeanticholinergic or antimuscarinic compounds, in particular ipratropiumbromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), andglycopyrrolate.

Suitable antihistamine drug substances include cetirizine hydrochloride,acetaminophen, clemastine fumarate, promethazine, loratidine,desloratidine, diphenhydramine and fexofenadine hydrochloride,activastine, astemizole, azelastine, ebastine, epinastine, mizolastineand tefenadine.

Other useful combinations of compounds of the invention withanti-inflammatory drugs are those with antagonists of chemokinereceptors, e.g. CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8,CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5antagonists such as Schering-Plough antagonists SC-351125, SCH-55700 andSCH-D, and Takeda antagonists such asN-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminium chloride (TAK-770).

The structure of the active compounds identified by code numbers,generic or trade names may be taken from the actual edition of thestandard compendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications).

A compound of the current invention may also be used in combination withknown therapeutic processes, for example, the administration of hormonesor radiation. In certain embodiments, a provided compound is used as aradiosensitizer, especially for the treatment of tumors which exhibitpoor sensitivity to radiotherapy.

A compound of the current invention can be administered alone or incombination with one or more other therapeutic compounds, possiblecombination therapy taking the form of fixed combinations or theadministration of a compound of the invention and one or more othertherapeutic compounds being staggered or given independently of oneanother, or the combined administration of fixed combinations and one ormore other therapeutic compounds. A compound of the current inventioncan besides or in addition be administered especially for tumor therapyin combination with chemotherapy, radiotherapy, immunotherapy,phototherapy, surgical intervention, or a combination of these.Long-term therapy is equally possible as is adjuvant therapy in thecontext of other treatment strategies, as described above. Otherpossible treatments are therapy to maintain the patient's status aftertumor regression, or even chemopreventive therapy, for example inpatients at risk.

Those additional agents may be administered separately from an inventivecompound-containing composition, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a compound of this invention in a single composition. Ifadministered as part of a multiple dosage regime, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another normally within five hours from one another.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with this invention. For example, a compound of thepresent invention may be administered with another therapeutic agentsimultaneously or sequentially in separate unit dosage forms or togetherin a single unit dosage form. Accordingly, the present inventionprovides a single unit dosage form comprising a compound of the currentinvention, an additional therapeutic agent, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.

The amount of both an inventive compound and additional therapeuticagent (in those compositions which comprise an additional therapeuticagent as described above) that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. Preferably,compositions of this invention should be formulated so that a dosage ofbetween 0.01-100 mg/kg body weight/day of an inventive compound can beadministered.

In those compositions which comprise an additional therapeutic agent,that additional therapeutic agent and the compound of this invention mayact synergistically. Therefore, the amount of additional therapeuticagent in such compositions will be less than that required in amonotherapy utilizing only that therapeutic agent. In such compositionsa dosage of between 0.01-1,000 μg/kg body weight/day of the additionaltherapeutic agent can be administered.

The amount of one or more other therapeutic agent present in thecompositions of this invention may be no more than the amount that wouldnormally be administered in a composition comprising that therapeuticagent as the only active agent. Preferably the amount of one or moreother therapeutic agent in the presently disclosed compositions willrange from about 50% to 100% of the amount normally present in acomposition comprising that agent as the only therapeutically activeagent. In some embodiments, one or more other therapeutic agent isadministered at a dosage of about 50%, about 55%, about 60%, about 65%,about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% ofthe amount normally administered for that agent. As used herein, thephrase “normally administered” means the amount an FDA approvedtherapeutic agent is approved for dosing per the FDA label insert.

The compounds of this invention, or pharmaceutical compositions thereof,may also be incorporated into compositions for coating an implantablemedical device, such as prostheses, artificial valves, vascular grafts,stents and catheters. Vascular stents, for example, have been used toovercome restenosis (re-narrowing of the vessel wall after injury).However, patients using stents or other implantable devices risk clotformation or platelet activation. These unwanted effects may beprevented or mitigated by pre-coating the device with a pharmaceuticallyacceptable composition comprising a kinase inhibitor. Implantabledevices coated with a compound of this invention are another embodimentof the present invention.

Exemplary Immuno-Oncology Agents

In some embodiments, one or more other therapeutic agent is animmuno-oncology agent. As used herein, the term “an immuno-oncologyagent” refers to an agent which is effective to enhance, stimulate,and/or up-regulate immune responses in a subject. In some embodiments,the administration of an immuno-oncology agent with a compound of theinvention has a synergic effect in treating a cancer.

An immuno-oncology agent can be, for example, a small molecule drug, anantibody, or a biologic or small molecule. Examples of biologicimmuno-oncology agents include, but are not limited to, cancer vaccines,antibodies, and cytokines. In some embodiments, an antibody is amonoclonal antibody. In some embodiments, a monoclonal antibody ishumanized or human.

In some embodiments, an immuno-oncology agent is (i) an agonist of astimulatory (including a co-stimulatory) receptor or (ii) an antagonistof an inhibitory (including a co-inhibitory) signal on T cells, both ofwhich result in amplifying antigen-specific T cell responses.

Certain of the stimulatory and inhibitory molecules are members of theimmunoglobulin super family (IgSF). One important family ofmembrane-bound ligands that bind to co-stimulatory or co-inhibitoryreceptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1),B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6.Another family of membrane bound ligands that bind to co-stimulatory orco-inhibitory receptors is the TNF family of molecules that bind tocognate TNF receptor family members, which includes CD40 and CD40F,OX-40, OX-40F, CD70, CD27F, CD30, CD30F, 4-1BBF, CD137 (4-1BB),TRAIF/Apo2-F, TRAIFR1/DR4, TRAIFR2/DR5, TRAIFR3, TRAIFR4, OPG, RANK,RANKE, TWEAKR/Fnl4, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR,LIGHT, DcR3, HVEM, VEGI/TF1A, TRAMP/DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1,Lymphotoxin α/TNFβ, TNFR2, TNFα, LTβR, Lymphotoxin α1β2, FAS, FASL,RELT, DR6, TROY, NGFR.

In some embodiments, an immuno-oncology agent is a cytokine thatinhibits T cell activation (e.g., IL-6, IL-10, TGF-β, VEGF, and otherimmunosuppressive cytokines) or a cytokine that stimulates T cellactivation, for stimulating an immune response.

In some embodiments, a combination of a compound of the invention and animmuno-oncology agent can stimulate T cell responses. In someembodiments, an immuno-oncology agent is: (i) an antagonist of a proteinthat inhibits T cell activation (e.g., immune checkpoint inhibitors)such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1,BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4; or (ii) an agonist of a protein thatstimulates T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD137),4-1BBL, ICOS, ICOS-L, Ox40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3and CD28H.

In some embodiments, an immuno-oncology agent is an antagonist ofinhibitory receptors on NK cells or an agonists of activating receptorson NK cells. In some embodiments, an immuno-oncology agent is anantagonists of KIR, such as lirilumab.

In some embodiments, an immuno-oncology agent is an agent that inhibitsor depletes macrophages or monocytes, including but not limited toCSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155(WO 2011/070024, US 2011/0165156, WO 2011/0107553, US 2012/0329997, WO2011/131407, US 2013/0005949, WO 2013/087699, US 2014/0336363, WO2013/119716, WO 2013/132044, US 2014/0079706) or FPA-008 (WO2011/140249, US 2011/0274683; WO 2013/169264; WO 2014/036357, US2014/0079699).

In some embodiments, an immuno-oncology agent is selected from agonisticagents that ligate positive costimulatory receptors, blocking agentsthat attenuate signaling through inhibitory receptors, antagonists, andone or more agents that increase systemically the frequency ofanti-tumor T cells, agents that overcome distinct immune suppressivepathways within the tumor microenvironment (e.g., block inhibitoryreceptor engagement (e.g., PD-L1/PD-1 interactions), deplete or inhibitTregs (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab)or by ex vivo anti-CD25 bead depletion), inhibit metabolic enzymes suchas IDO, or reverse/prevent T cell energy or exhaustion) and agents thattrigger innate immune activation and/or inflammation at tumor sites.

In some embodiments, an immuno-oncology agent is a CTUA-4 antagonist. Insome embodiments, a CTUA-4 antagonist is an antagonistic CTUA-4antibody. In some embodiments, an antagonistic CTUA-4 antibody is YERVOY(ipilimumab) or tremelimumab.

In some embodiments, an immuno-oncology agent is a PD-1 antagonist. Insome embodiments, a PD-1 antagonist is administered by infusion. In someembodiments, an immuno-oncology agent is an antibody or anantigen-binding portion thereof that binds specifically to a ProgrammedDeath-1 (PD-1) receptor and inhibits PD-1 activity. In some embodiments,a PD-1 antagonist is an antagonistic PD-1 antibody. In some embodiments,an antagonistic PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA(pembrolizumab), or MEDI-0680 (AMP-514; WO2012/145493). In someembodiments, an immuno-oncology agent may be pidilizumab (CT-011). Insome embodiments, an immuno-oncology agent is a recombinant proteincomposed of the extracellular domain of PD-L2 (B7-DC) fused to the Fcportion of IgG1, called AMP-224.

In some embodiments, an immuno-oncology agent is a PD-L1 antagonist. Insome embodiments, a PD-L1 antagonist is an antagonistic PD-L1 antibody.In some embodiments, a PD-L1 antibody is MPDL3280A (RG7446; WO2010/077634, US 2010/0203056), durvalumab (MEDI4736), BMS-936559 (WO2007/005874, US 2009/0055944), and MSB0010718C (WO 2013/079174, US2014/0341917).

In some embodiments, an immuno-oncology agent is a UAG-3 antagonist. Insome embodiments, a UAG-3 antagonist is an antagonistic UAG-3 antibody.In some embodiments, a UAG3 antibody is BMS-986016 (WO 2010/019570, US2010/0150892, WO 2014/008218, US 2014/0093511), or IMP-731 or IMP-321(WO 2008/132601, US 2010/0233183, WO 2009/044273, US 2011/0008331).

In some embodiments, an immuno-oncology agent is a CD137 (4-1BB)agonist. In some embodiments, a CD137 (4-1BB) agonist is an agonisticCD137 antibody. In some embodiments, a CD137 antibody is urelumab orPF-05082566 (WO12/32433).

In some embodiments, an immuno-oncology agent is a GITR agonist. In someembodiments, a GITR agonist is an agonistic GITR antibody. In someembodiments, a GITR antibody is BMS-986153, BMS-986156, TRX-518 (WO2006/105021, US 2007/0098719, WO 2009/009116, US 2009/0136494), orMK-4166 (WO 2011/028683, US 2012/0189639).

In some embodiments, an immuno-oncology agent is an indoleamine(2,3)-dioxygenase (IDO) antagonist. In some embodiments, an IDOantagonist is selected from epacadostat (INCB024360, Incyte); indoximod(NUG-8189, NewUink Genetics Corporation); capmanitib (INC280, Novartis);GDC-0919 (Genentech/Roche); PF-06840003 (Pfizer); BMS:F001287(Bristol-Myers Squibb); Phy906/KD108 (Phytoceutica); an enzyme thatbreaks down kynurenine (Kynase, Kyn Therapeutics); and NUG-919 (WO2009/073620, US 2011/053941, WO 2009/132238, US 2011/136796, WO2011/056652, US 2012/277217, WO 2012/142237, US 2014/066625).

In some embodiments, an immuno-oncology agent is an Ox40 agonist. Insome embodiments, an Ox40 agonist is an agonistic Ox40 antibody. In someembodiments, an Ox40 antibody is MEDI-6383 or MEDI-6469.

In some embodiments, an immuno-oncology agent is an OX40L antagonist. Insome embodiments, an OX40L antagonist is an antagonistic Ox40 antibody.In some embodiments, an OX40L antagonist is RG-7888 (WO 2006/029879,U.S. Pat. No. 7,501,496).

In some embodiments, an immuno-oncology agent is a CD40 agonist. In someembodiments, a CD40 agonist is an agonistic CD40 antibody. In someembodiments, an immuno-oncology agent is a CD40 antagonist. In someembodiments, a CD40 antagonist is an antagonistic CD40 antibody. In someembodiments, a CD40 antibody is lucatumumab or dacetuzumab.

In some embodiments, an immuno-oncology agent is a CD27 agonist. In someembodiments, a CD27 agonist is an agonistic CD27 antibody. In someembodiments, a CD27 antibody is varlilumab.

In some embodiments, an immuno-oncology agent is MGA271 (to B7H3) (WO2011/109400, US 2013/0149236).

In some embodiments, an immuno-oncology agent is abagovomab,adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab,atezolimab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab,epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab,ipilimumab, isatuximab, lambrolizumab, MED 14736, MPDL3280A, nivolumab,obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab,pidilizumab, rituximab, ticilimumab, samalizumab, or tremelimumab.

In some embodiments, an immuno-oncology agent is an immunostimulatoryagent. For example, antibodies blocking the PD-1 and PD-L1 inhibitoryaxis can unleash activated tumor -reactive T cells and have been shownin clinical trials to induce durable anti-tumor responses in increasingnumbers of tumor histologies, including some tumor types thatconventionally have not been considered immunotherapy sensitive. See,e.g., Okazaki, T. et al. (2013) Nat. Immunol. 14, 1212-1218; Zou et al.(2016) Sci. Transl. Med. 8. The anti-PD-1 antibody nivolumab (Opdivo®,Bristol-Myers Squibb, also known as ONO-4538, MDX1106 and BMS-936558),has shown potential to improve the overall survival in patients with RCCwho had experienced disease progression during or after prioranti-angiogenic therapy.

In some embodiments, the immunomodulatory therapeutic specificallyinduces apoptosis of tumor cells. Approved immunomodulatory therapeuticswhich may be used in the present invention include pomalidomide(Pomalyst®, Celgene); lenalidomide (Revlimid®, Celgene); ingenolmebutate (Picato®, LEO Pharma).

In some embodiments, an immuno-oncology agent is a cancer vaccine. Insome embodiments, the cancer vaccine is selected from sipuleucel-T(Provenge®, Dendreon/Valeant Pharmaceuticals), which has been approvedfor treatment of asymptomatic, or minimally symptomatic metastaticcastrate-resistant (hormone-refractory) prostate cancer; and talimogenelaherparepvec (Imlygic®, BioVex/Amgen, previously known as T-VEC), agenetically modified oncolytic viral therapy approved for treatment ofunresectable cutaneous, subcutaneous and nodal lesions in melanoma. Insome embodiments, an immuno-oncology agent is selected from an oncolyticviral therapy such as pexastimogene devacirepvec (PexaVec/JX-594,SillaJen/formerly Jennerex Biotherapeutics), a thymidine kinase- (TK-)deficient vaccinia virus engineered to express GM-CSF, forhepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312);pelareorep (Reolysin®, Oncolytics Biotech), a variant of respiratoryenteric orphan virus (reovirus) which does not replicate in cells thatare not RAS-activated, in numerous cancers, including colorectal cancer(NCT01622543); prostate cancer (NCT01619813); head and neck squamouscell cancer (NCT01166542); pancreatic adenocarcinoma (NCT00998322); andnon-small cell lung cancer (NSCLC) (NCT 00861627); enadenotucirev(NG-348, PsiOxus, formerly known as ColoAdl), an adenovirus engineeredto express a full length CD80 and an antibody fragment specific for theT-cell receptor CD3 protein, in ovarian cancer (NCT02028117); metastaticor advanced epithelial tumors such as in colorectal cancer, bladdercancer, head and neck squamous cell carcinoma and salivary gland cancer(NCT02636036); ONCOS-102 (Targovax/formerly Oncos), an adenovirusengineered to express GM-CSF, in melanoma (NCT03003676); and peritonealdisease, colorectal cancer or ovarian cancer (NCT02963831); GL-ONC1(GLV-1h68/GLV-1h153, Genelux GmbH), vaccinia viruses engineered toexpress beta-galactosidase (beta-gal)/beta-glucoronidase orbeta-gal/human sodium iodide symporter (hNIS), respectively, werestudied in peritoneal carcinomatosis (NCT01443260); fallopian tubecancer, ovarian cancer (NCT 02759588); or CG0070 (Cold Genesys), anadenovirus engineered to express GM-CSF, in bladder cancer(NCT02365818).

In some embodiments, an immuno-oncology agent is selected from JX-929(SillaJen/formerly Jennerex Biotherapeutics), a TK- and vaccinia growthfactor-deficient vaccinia virus engineered to express cytosinedeaminase, which is able to convert the prodrug 5-fluorocytosine to thecytotoxic drug 5-fluorouracil; TG01 and TG02 (Targovax/formerly Oncos),peptide-based immunotherapy agents targeted for difficult-to-treat RASmutations; and TILT-123 (TILT Biotherapeutics), an engineered adenovirusdesignated: Ad5/3-E2F-delta24-hTNFα-IRES-hIL20; and VSV-GP(ViraTherapeutics) a vesicular stomatitis virus (VSV) engineered toexpress the glycoprotein (GP) of lymphocytic choriomeningitis virus(LCMV), which can be further engineered to express antigens designed toraise an antigen-specific CD8⁺ T cell response.

In some embodiments, an immuno-oncology agent is a T-cell engineered toexpress a chimeric antigen receptor, or CAR. The T-cells engineered toexpress such chimeric antigen receptor are referred to as a CAR-T cells.

CARs have been constructed that consist of binding domains, which may bederived from natural ligands, single chain variable fragments (scFv)derived from monoclonal antibodies specific for cell-surface antigens,fused to endodomains that are the functional end of the T-cell receptor(TCR), such as the CD3-zeta signaling domain from TCRs, which is capableof generating an activation signal in T lymphocytes. Upon antigenbinding, such CARs link to endogenous signaling pathways in the effectorcell and generate activating signals similar to those initiated by theTCR complex.

For example, in some embodiments the CAR-T cell is one of thosedescribed in U.S. Pat. No. 8,906,682, the entirety of each of which isherein incorporated by reference, which discloses CAR-T cells engineeredto comprise an extracellular domain having an antigen binding domain(such as a domain that binds to CD19), fused to an intracellularsignaling domain of the T cell antigen receptor complex zeta chain (suchas CD3 zeta). When expressed in the T cell, the CAR is able to redirectantigen recognition based on the antigen binding specificity. In thecase of CD19, the antigen is expressed on malignant B cells. Over 200clinical trials are currently in progress employing CAR-T in a widerange of indications.[https://clinicaltrials.gov/ct2/results?term=chimeric+antigen+receptors&pg=1].

In some embodiments, an immunostimulatory agent is an activator ofretinoic acid receptor-related orphan receptor γ (RORγt). RORγt is atranscription factor with key roles in the differentiation andmaintenance of Type 17 effector subsets of CD4+ (Th17) and CD8+ (Tc17) Tcells, as well as the differentiation of IL-17 expressing innate immunecell subpopulations such as NK cells. In some embodiments, an activatorof RORγt is LYC-55716 (Lycera), which is currently being evaluated inclinical trials for the treatment of solid tumors (NCT02929862).

In some embodiments, an immunostimulatory agent is an agonist oractivator of a toll-like receptor (TLR). Suitable activators of TLRsinclude an agonist or activator of TLR9 such as SD-101 (Dynavax). SD-101is an immunostimulatory CpG which is being studied for B-cell,follicular and other lymphomas (NCT02254772). Agonists or activators ofTLR8 which may be used in the present invention include motolimod(VTX-2337, VentiRx Pharmaceuticals) which is being studied for squamouscell cancer of the head and neck (NCT02124850) and ovarian cancer(NCT02431559).

Other immuno-oncology agents that may be used in the present inventioninclude urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137monoclonal antibody; varlilumab (CDX-1127, Celldex Therapeutics), ananti-CD27 monoclonal antibody; BMS-986178 (Bristol-Myers Squibb), ananti-Ox40 monoclonal antibody; lirilumab (IPH2102/BMS-986015, InnatePharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody;monalizumab (IPH2201, Innate Pharma, AstraZeneca) an anti-NKG2Amonoclonal antibody; andecaliximab (GS-5745, Gilead Sciences), ananti-MMP9 antibody; MK-4166 (Merck & Co.), an anti-GITR monoclonalantibody.

In some embodiments, an immunostimulatory agent is selected fromelotuzumab, mifamurtide, an agonist or activator of a toll-likereceptor, and an activator of RORγt.

In some embodiments, an immunostimulatory therapeutic is recombinanthuman interleukin 15 (rhIL-15). rhIL-15 has been tested in the clinic asa therapy for melanoma and renal cell carcinoma (NCT01021059 andNCT01369888) and leukemias (NCT02689453). In some embodiments, animmunostimulatory agent is recombinant human interleukin 12 (rhIL-12).In some embodiments, an IL-15 based immunotherapeutic is heterodimericIL-15 (hetIL-15, Novartis/Admune), a fusion complex composed of asynthetic form of endogenous IL-15 complexed to the soluble IL-15binding protein IL-15 receptor alpha chain (IL15:sIL-15RA), which hasbeen tested in Phase 1 clinical trials for melanoma, renal cellcarcinoma, non-small cell lung cancer and head and neck squamous cellcarcinoma (NCT02452268). In some embodiments, a recombinant humaninterleukin 12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724,or NCT02542124.

In some embodiments, an immuno-oncology agent is selected from thosedescripted in Jerry L. Adams ET. AL., “Big opportunities for smallmolecules in immuno-oncology,” Cancer Therapy 2015, Vol. 14, pages603-622, the content of which is incorporated herein by reference in itsentirety. In some embodiment, an immuno-oncology agent is selected fromthe examples described in Table 1 of Jerry L. Adams ET. AL. In someembodiments, an immuno-oncology agent is a small molecule targeting animmuno-oncology target selected from those listed in Table 2 of Jerry L.Adams ET. AL. In some embodiments, an immuno-oncology agent is a smallmolecule agent selected from those listed in Table 2 of Jerry L. AdamsET. AL.

In some embodiments, an immuno-oncology agent is selected from the smallmolecule immuno-oncology agents described in Peter L. Toogood, “Smallmolecule immuno-oncology therapeutic agents,” Bioorganic & MedicinalChemistry Letters 2018, Vol. 28, pages 319-329, the content of which isincorporated herein by reference in its entirety. In some embodiments,an immuno-oncology agent is an agent targeting the pathways as describedin Peter L. Toogood.

In some embodiments, an immuno-oncology agent is selected from thosedescribed in Sandra L. Ross et al., “Bispecific T cell engager (BiTE®)antibody constructs can mediate bystander tumor cell killing”, PLoS ONE12(8): eO 183390, the content of which is incorporated herein byreference in its entirety. In some embodiments, an immuno-oncology agentis a bispecific T cell engager (BiTE®) antibody construct. In someembodiments, a bispecific T cell engager (BiTE®) antibody construct is aCD19/CD3 bispecific antibody construct. In some embodiments, abispecific T cell engager (BiTE®) antibody construct is an EGFR/CD3bispecific antibody construct. In some embodiments, a bispecific T cellengager (BiTE®) antibody construct activates T cells. In someembodiments, a bispecific T cell engager (BiTE®) antibody constructactivates T cells, which release cytokines inducing upregulation ofintercellular adhesion molecule 1 (ICAM-1) and FAS on bystander cells.In some embodiments, a bispecific T cell engager (BiTE®) antibodyconstruct activates T cells which result in induced bystander celllysis. In some embodiments, the bystander cells are in solid tumors. Insome embodiments, the bystander cells being lysed are in proximity tothe BiTE®-activated T cells. In some embodiment, the bystander cellscomprises tumor -associated antigen (TAA) negative cancer cells. In someembodiment, the bystander cells comprise EGFR-negative cancer cells. Insome embodiments, an immuno-oncology agent is an antibody which blocksthe PD-L1/PD1 axis and/or CTLA4. In some embodiments, an immuno-oncologyagent is an ex-vivo expanded tumor -infiltrating T cell. In someembodiments, an immuno-oncology agent is a bispecific antibody constructor chimeric antigen receptors (CARs) that directly connect T cells withtumor -associated surface antigens (TAAs).

Exemplary Immune Checkpoint Inhibitors

In some embodiments, an immuno-oncology agent is an immune checkpointinhibitor as described herein.

The term “checkpoint inhibitor” as used herein relates to agents usefulin preventing cancer cells from avoiding the immune system of thepatient. One of the major mechanisms of anti-tumor immunity subversionis known as “T-cell exhaustion,” which results from chronic exposure toantigens that has led to up-regulation of inhibitory receptors. Theseinhibitory receptors serve as immune checkpoints in order to preventuncontrolled immune reactions.

PD-1 and co-inhibitory receptors such as cytotoxic T-lymphocyte antigen4 (CTLA-4, B and T Lymphocyte Attenuator (BTLA; CD272), T cellImmunoglobulin and Mucin domain-3 (Tim-3), Lymphocyte Activation Gene-3(Lag-3; CD223), and others are often referred to as a checkpointregulators. They act as molecular “gatekeepers” that allow extracellularinformation to dictate whether cell cycle progression and otherintracellular signaling processes should proceed.

In some embodiments, an immune checkpoint inhibitor is an antibody toPD-1. PD-1 binds to the programmed cell death 1 receptor (PD-1) toprevent the receptor from binding to the inhibitory ligand PDL-1, thusoverriding the ability of tumors to suppress the host anti-tumor immuneresponse.

In one aspect, the checkpoint inhibitor is a biologic therapeutic or asmall molecule. In another aspect, the checkpoint inhibitor is amonoclonal antibody, a humanized antibody, a fully human antibody, afusion protein or a combination thereof. In a further aspect, thecheckpoint inhibitor inhibits a checkpoint protein selected from CTLA-4,PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR,2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or acombination thereof. In an additional aspect, the checkpoint inhibitorinteracts with a ligand of a checkpoint protein selected from CTLA-4,PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR,2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or acombination thereof. In an aspect, the checkpoint inhibitor is animmunostimulatory agent, a T cell growth factor, an interleukin, anantibody, a vaccine or a combination thereof. In a further aspect, theinterleukin is IL-7 or IL-15. In a specific aspect, the interleukin isglycosylated IL-7. In an additional aspect, the vaccine is a dendriticcell (DC) vaccine.

Checkpoint inhibitors include any agent that blocks or inhibits in astatistically significant manner, the inhibitory pathways of the immunesystem. Such inhibitors may include small molecule inhibitors or mayinclude antibodies, or antigen binding fragments thereof, that bind toand block or inhibit immune checkpoint receptors or antibodies that bindto and block or inhibit immune checkpoint receptor ligands. Illustrativecheckpoint molecules that may be targeted for blocking or inhibitioninclude, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4,BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belongs to the CD2 familyof molecules and is expressed on all NK, y5, and memory CD8⁺ (αβ) Tcells), CD160 (also referred to as BY55), CGEN-15049, CHK 1 and CHK2kinases, A2aR, and various B-7 family ligands. B7 family ligandsinclude, but are not limited to, B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3,B7-H4, B7-H5, B7-H6 and B7-H7. Checkpoint inhibitors include antibodies,or antigen binding fragments thereof, other binding proteins, biologictherapeutics, or small molecules, that bind to and block or inhibit theactivity of one or more of CTLA-4, PDL1, PDL2, PD 1, BTLA, HVEM, TIM3,GAL9, LAG3, VISTA, KIR, 2B4, CD 160 and CGEN-15049. Illustrative immunecheckpoint inhibitors include Tremelimumab (CTLA-4 blocking antibody),anti-OX40, PD-L1 monoclonal Antibody (Anti-B7-H1; MEDI4736), MK-3475(PD-1 blocker), Nivolumab (anti-PD1 antibody), CT-011 (anti-PD1antibody), BY55 monoclonal antibody, AMP224 (anti-PDL1 antibody),BMS-936559 (anti-PDL1 antibody), MPLDL3280A (anti-PDL1 antibody),MSB0010718C (anti-PDL1 antibody), and ipilimumab (anti-CTLA-4 checkpointinhibitor). Checkpoint protein ligands include, but are not limited toPD-L1, PD-L2, B7-H3, B7-H4, CD28, CD86 and TIM-3.

In certain embodiments, the immune checkpoint inhibitor is selected froma PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist. In someembodiments, the checkpoint inhibitor is selected from the groupconsisting of nivolumab (Opdivo®), ipilimumab (Yervoy®), andpembrolizumab (Keytruda®). In some embodiments, the checkpoint inhibitoris selected from nivolumab (anti-PD-1 antibody, Opdivo®, Bristol-MyersSquibb); pembrolizumab (anti-PD-1 antibody, Keytruda®, Merck);ipilimumab (anti-CTLA-4 antibody, Yervoy®, Bristol-Myers Squibb);durvalumab (anti-PD-L1 antibody, Imfinzi®, AstraZeneca); andatezolizumab (anti-PD-L1 antibody, Tecentriq®, Genentech).

In some embodiments, the checkpoint inhibitor is selected from the groupconsisting of lambrolizumab (MK-3475), nivolumab (BMS-936558),pidilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A,BMS-936559, ipilimumab, lirlumab, IPH2101, pembrolizumab (Keytruda®),and tremelimumab.

In some embodiments, an immune checkpoint inhibitor is REGN2810(Regeneron), an anti-PD-1 antibody tested in patients with basal cellcarcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cellcarcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma(NCT03002376); pidilizumab (CureTech), also known as CT-011, an antibodythat binds to PD-1, in clinical trials for diffuse large B-cell lymphomaand multiple myeloma; avelumab (Bavencio®, Pfizer/Merck KGaA), alsoknown as MSB0010718C), a fully human IgG1 anti-PD-L1 antibody, inclinical trials for non-small cell lung cancer, Merkel cell carcinoma,mesothelioma, solid tumors, renal cancer, ovarian cancer, bladdercancer, head and neck cancer, and gastric cancer; or PDR001 (Novartis),an inhibitory antibody that binds to PD-1, in clinical trials fornon-small cell lung cancer, melanoma, triple negative breast cancer andadvanced or metastatic solid tumors. Tremelimumab (CP-675,206;Astrazeneca) is a fully human monoclonal antibody against CTLA-4 thathas been in studied in clinical trials for a number of indications,including: mesothelioma, colorectal cancer, kidney cancer, breastcancer, lung cancer and non-small cell lung cancer, pancreatic ductaladenocarcinoma, pancreatic cancer, germ cell cancer, squamous cellcancer of the head and neck, hepatocellular carcinoma, prostate cancer,endometrial cancer, metastatic cancer in the liver, liver cancer, largeB-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplasticthyroid cancer, urothelial cancer, fallopian tube cancer, multiplemyeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884(Agenus) is an anti-CTLA4 antibody that is being studied in Phase 1clinical trials for advanced solid tumors (NCT02694822).

In some embodiments, a checkpoint inhibitor is an inhibitor of T-cellimmunoglobulin mucin containing protein-3 (TIM-3). TIM-3 inhibitors thatmay be used in the present invention include TSR-022, LY3321367 andMBG453. TSR-022 (Tesaro) is an anti-TIM-3 antibody which is beingstudied in solid tumors (NCT02817633). LY3321367 (Eh Lilly) is ananti-TIM-3 antibody which is being studied in solid tumors(NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody which isbeing studied in advanced malignancies (NCT02608268).

In some embodiments, a checkpoint inhibitor is an inhibitor of T cellimmunoreceptor with Ig and ITIM domains, or TIGIT, an immune receptor oncertain T cells and NK cells. TIGIT inhibitors that may be used in thepresent invention include BMS-986207 (Bristol-Myers Squibb), ananti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); andanti-TIGIT monoclonal antibody (NCT03119428).

In some embodiments, a checkpoint inhibitor is an inhibitor ofLymphocyte Activation Gene-3 (LAG-3). LAG-3 inhibitors that may be usedin the present invention include BMS-986016 and REGN3767 and IMP321.BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is beingstudied in glioblastoma and gliosarcoma (NCT02658981). REGN3767(Regeneron), is also an anti-LAG-3 antibody, and is being studied inmalignancies (NCT03005782). IMP321 (Immutep S.A.) is an LAG-3-Ig fusionprotein, being studied in melanoma (NCT02676869); adenocarcinoma(NCT02614833); and metastatic breast cancer (NCT00349934).

Checkpoint inhibitors that may be used in the present invention includeOx40 agonists. Ox40 agonists that are being studied in clinical trialsinclude PL-04518600/PL-8600 (Pfizer), an agonistic anti-Ox40 antibody,in metastatic kidney cancer (NCT03092856) and advanced cancers andneoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck), an agonisticanti-OX40 antibody, in Phase 1 cancer trials (NCT02528357); MEDI0562(Medimmune/AstraZeneca), an agonistic anti-OX40 antibody, in advancedsolid tumors (NCT02318394 and NCT02705482); MEDI6469, an agonisticanti-OX40 antibody (Medimmune/AstraZeneca), in patients with colorectalcancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer(NCT02274155) and metastatic prostate cancer (NCT01303705); andBMS-986178 (Bristol-Myers Squibb) an agonistic anti-OX40 antibody, inadvanced cancers (NCT02737475).

Checkpoint inhibitors that may be used in the present invention includeCD137 (also called 4-1BB) agonists. CD137 agonists that are beingstudied in clinical trials include utomilumab (PF-05082566, Pfizer) anagonistic anti-CD137 antibody, in diffuse large B-cell lymphoma(NCT02951156) and in advanced cancers and neoplasms (NCT02554812 andNCT05082566); urelumab (BMS-663513, Bristol-Myers Squibb), an agonisticanti-CD137 antibody, in melanoma and skin cancer (NCT02652455) andglioblastoma and gliosarcoma (NCT02658981).

Checkpoint inhibitors that may be used in the present invention includeCD27 agonists. CD27 agonists that are being studied in clinical trialsinclude varlilumab (CDX-1127, Celldex Therapeutics) an agonisticanti-CD27 antibody, in squamous cell head and neck cancer, ovariancarcinoma, colorectal cancer, renal cell cancer, and glioblastoma(NCT02335918); lymphomas (NCT01460134); and glioma and astrocytoma(NCT02924038).

Checkpoint inhibitors that may be used in the present invention includeglucocorticoid-induced tumor necrosis factor receptor (GITR) agonists.GITR agonists that are being studied in clinical trials include TRX518(Leap Therapeutics), an agonistic anti-GITR antibody, in malignantmelanoma and other malignant solid tumors (NCT01239134 and NCT02628574);GWN323 (Novartis), an agonistic anti-GITR antibody, in solid tumors andlymphoma (NCT 02740270); INCAGN01876 (Incyte/Agenus), an agonisticanti-GITR antibody, in advanced cancers (NCT02697591 and NCT03126110);MK-4166 (Merck), an agonistic anti-GITR antibody, in solid tumors(NCT02132754) and MEDI1873 (Medimmune/AstraZeneca), an agonistichexameric GITR-ligand molecule with a human IgG1 Fc domain, in advancedsolid tumors (NCT02583165).

Checkpoint inhibitors that may be used in the present invention includeinducible T-cell co-stimulator (ICOS, also known as CD278) agonists.ICOS agonists that are being studied in clinical trials include MEDI-570(Medimmune), an agonistic anti-ICOS antibody, in lymphomas(NCT02520791); GSK3359609 (Merck), an agonistic anti-ICOS antibody, inPhase 1 (NCT02723955); JTX-2011 (Jounce Therapeutics), an agonisticanti-ICOS antibody, in Phase 1 (NCT02904226).

Checkpoint inhibitors that may be used in the present invention includekiller IgG-like receptor (KIR) inhibitors. KIR inhibitors that are beingstudied in clinical trials include lirilumab (IPH2102/BMS-986015, InnatePharma/Bristol-Myers Squibb), an anti-KIR antibody, in leukemias(NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma(NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, InnatePharma) in myeloma (NCT01222286 and NCT01217203); and IPH4102 (InnatePharma), an anti-KIR antibody that binds to three domains of the longcytoplasmic tail (KIR3DL2), in lymphoma (NCT02593045).

Checkpoint inhibitors that may be used in the present invention includeCD47 inhibitors of interaction between CD47 and signal regulatoryprotein alpha (SIRPa). CD47/SIRPa inhibitors that are being studied inclinical trials include ALX-148 (Alexo Therapeutics), an antagonisticvariant of (SIRPa) that binds to CD47 and prevents CD47/SIRPa-mediatedsignaling, in phase 1 (NCT03013218); TTI-621 (SIRPa-Fc, TrilliumTherapeutics), a soluble recombinant fusion protein created by linkingthe N-terminal CD47-binding domain of SIRPa with the Fc domain of humanIgG1, acts by binding human CD47, and preventing it from delivering its“do not eat” signal to macrophages, is in clinical trials in Phase 1(NCT02890368 and NCT02663518); CC-90002 (Celgene), an anti-CD47antibody, in leukemias (NCT02641002); and Hu5F9-G4 (Forty Seven, Inc.),in colorectal neoplasms and solid tumors (NCT02953782), acute myeloidleukemia (NCT02678338) and lymphoma (NCT02953509).

Checkpoint inhibitors that may be used in the present invention includeCD73 inhibitors. CD73 inhibitors that are being studied in clinicaltrials include MEDI9447 (Medimmune), an anti-CD73 antibody, in solidtumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), ananti-CD73 antibody, in solid tumors (NCT02754141).

Checkpoint inhibitors that may be used in the present invention includeagonists of stimulator of interferon genes protein (STING, also known astransmembrane protein 173, or TMEM173). Agonists of STING that are beingstudied in clinical trials include MK-1454 (Merck), an agonisticsynthetic cyclic dinucleotide, in lymphoma (NCT03010176); and ADU-S100(MIW815, Aduro Biotech/Novartis), an agonistic synthetic cyclicdinucleotide, in Phase 1 (NCT02675439 and NCT03172936).

Checkpoint inhibitors that may be used in the present invention includeCSF1R inhibitors. CSF1R inhibitors that are being studied in clinicaltrials include pexidartinib (PLX3397, Plexxikon), a CSF1R small moleculeinhibitor, in colorectal cancer, pancreatic cancer, metastatic andadvanced cancers (NCT02777710) and melanoma, non-small cell lung cancer,squamous cell head and neck cancer, gastrointestinal stromal tumor(GIST) and ovarian cancer (NCT02452424); and IMC-CS4 (LY3022855, Lilly),an anti-CSF-1R antibody, in pancreatic cancer (NCT03153410), melanoma(NCT03101254), and solid tumors (NCT02718911); and BLZ945(4-[2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazol-6-yloxyl]-pyridine-2-carboxylicacid methylamide, Novartis), an orally available inhibitor of CSF1R, inadvanced solid tumors (NCT02829723).

Checkpoint inhibitors that may be used in the present invention includeNKG2A receptor inhibitors. NKG2A receptor inhibitors that are beingstudied in clinical trials include monalizumab (IPH2201, Innate Pharma),an anti-NKG2A antibody, in head and neck neoplasms (NCT02643550) andchronic lymphocytic leukemia (NCT02557516).

In some embodiments, the immune checkpoint inhibitor is selected fromnivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab,atezolizumab, or pidilizumab.

EXEMPLIFICATION Abbreviations

-   -   Ac: acetyl    -   AcOH: acetic acid    -   ACN: acetonitrile    -   Ad: adamantly    -   AIBN: 2,2′-azo bisisobutyronitrile    -   Anhyd: anhydrous    -   Aq: aqueous    -   B₂Pin₂: bis (pinacolato)diboron        -4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)    -   BINAP: 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl    -   BH₃: Borane    -   Bn: benzyl    -   Boc: tert-butoxycarbonyl    -   BOC₂O: di-tert-butyl dicarbonate    -   BPO: benzoyl peroxide    -   ^(n)BuOH: n-butanol    -   CDI: carbonyldiimidazole    -   COD: cyclooctadiene    -   d: days    -   DABCO: 1,4-diazobicyclo[2.2.2]octane    -   DAST: diethylaminosulfur trifluoride    -   dba: dibenzylideneacetone    -   DBU: 1,8-diazobicyclo[5.4.0]undec-7-ene    -   DCE: 1,2-dichloroethane    -   DCM: dichloromethane    -   DEA: diethylamine    -   DHP: dihydropyran    -   DIBAL-H: diisobutylaluminum hydride    -   DIPA: diisopropylamine    -   DIPEA or DIEA: N,N-diisopropylethylamine    -   DMA: N,N-dimethylacetamide    -   DME: 1,2-dimethoxyethane    -   DMAP: 4-dimethylaminopyridine    -   DMF: N,N-dimethylformamide    -   DMP: Dess-Martin periodinane    -   DMSO-dimethyl sulfoxide    -   DPPA: diphenylphosphoryl azide    -   dppf: 1,1′-bis(diphenylphosphino)ferrocene    -   EDC or EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide        hydrochloride    -   ee: enantiomeric excess    -   ESE electrospray ionization    -   EA: ethyl acetate    -   EtOAc: ethyl acetate    -   EtOH: ethanol    -   FA: formic acid    -   h or hrs: hours    -   HATU: N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium        hexafluorophosphate    -   HCl: hydrochloric acid    -   HPLC: high performance liquid chromatography    -   HOAc: acetic acid    -   IBX: 2-iodoxybenzoic acid    -   IPA: isopropyl alcohol    -   KHMDS: potassium hexamethyldisilazide    -   K₂CO₃: potassium carbonate    -   LAH: lithium aluminum hydride    -   LDA: lithium diisopropylamide    -   m-CPBA: meta-chloroperbenzoic acid    -   M: molar    -   MeCN: acetonitrile    -   MeOH: methanol    -   Me₂S: dimethyl sulfide    -   MeONa: sodium methylate    -   MeE iodomethane    -   min: minutes    -   mL: milliliters    -   mM: millimolar    -   mmol: millimoles    -   MPa: megapascal    -   MOMCl: methyl chloromethyl ether    -   MsCl: methanesulfonyl chloride    -   MTBE: methyl tert-butyl ether    -   nBuLi: n-butyllithium    -   NaNO₂: sodium nitrite    -   NaOH: sodium hydroxide    -   Na₂SO₄: sodium sulfate    -   NBS: N-bromosuccinimide    -   NCS: N-chlorosuccinimide    -   NFSI: N-Fluorobenzenesulfonimide    -   NMO: N-methylmorpholine N-oxide    -   NMP: N-methylpyrrolidine    -   NMR: Nuclear Magnetic Resonance    -   ° C.: degrees Celsius    -   Pd/C: Palladium on Carbon    -   Pd(OAc)₂: Palladium Acetate    -   PBS: phosphate buffered saline    -   PE: petroleum ether    -   POCl₃: phosphorus oxychloride    -   PPh₃: triphenylphosphine    -   PyBOP: (Benzotriazol-1-yloxy)tripyrrolidinophosphonium        hexafluorophosphate    -   Rel: relative    -   R.T. or rt: room temperature    -   sat: saturated    -   SEMCl: chloromethyl-2-trimethylsilylethyl ether    -   SFC: supercritical fluid chromatography    -   SOCl₂: sulfur dichloride    -   tBuOK: potassium tert-butoxide    -   TBAB: tetrabutylammonium bromide    -   TBAI: tetrabutylammonium iodide    -   TEA: triethylamine    -   Tf: trifluoromethane sulfonate    -   TfAA, TFMSA or Tf₂O: trifluoromethanesulfonic anhydride    -   TFA: trifluoracetic acid    -   TIPS: triisopropylsilyl    -   THF: tetrahydrofuran    -   THP: tetrahydropyran    -   TLC: thin layer chromatography    -   TMEDA: tetramethylethylenediamine    -   pTSA: para-toluenesulfonic acid    -   wt: weight    -   Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

General Synthetic Methods

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees centigrade. If not mentioned otherwise, all evaporations wereperformed under reduced pressure, preferably between about 15 mm Hg and100 mm Hg (=20-133 mbar). The structure of final products, intermediatesand starting materials was confirmed by standard analytical methods,e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR,NMR. Abbreviations used are those conventional in the art.

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents, and catalysts utilized to synthesis thecompounds of the present invention were either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art (Houben-Weyl 4th Ed. 1952, Methods of OrganicSynthesis, Thieme, Volume 21). Further, the compounds of the presentinvention can be produced by organic synthesis methods known to one ofordinary skill in the art as shown in the following examples.

All reactions were carried out under nitrogen or argon unless otherwisestated.

Proton NMR (¹H NMR) was conducted in deuterated solvent. In certaincompounds disclosed herein, one or more ¹H shifts overlap with residualproteo solvent signals; these signals have not been reported in theexperimental provided hereinafter.

TABLE 2 Analytical instruments LCMS Shimadzu UFLC MS: LCMS-2020 AgilentTechnologies 1200 series MS: Agilent Technologies 6110 AgilentTechnologies 1200 series MS: LC/MSD VL NMR BRUKER AVANCE III/400;Frequency (MHz) 400.13; Nucleus: 1H; Number of Transients: 8 Prep-HPLCGilson GX-281 systems: instruments GX-A, GX-B, GX-C, GX-D, GX-E, GX-F,GX-G and GX-H GCMS SHIMADZU GCMS-QP2010 Ultra Analytical cSFC AgilentTechnologies 1290 Infinity Prep-cSFC Waters SFC Prep 80

For acidic FCMS data: FCMS was recorded on an Agilent 1200 Series FC/MSDor Shimadzu FCMS2020 equipped with electro-spray ionization andquadruple MS detector [ES+ve to give MH⁺] and equipped with ChromolithFlash RP-18e 25*2.0 mm, eluting with 0.0375 vol % TFA in water (solventA) and 0.01875 vol % TFA in acetonitrile (solvent B). Other FCMS wasrecorded on an Agilent 1290 Infinity RRFC attached with Agilent 6120Mass detector. The column used was BEH C18 50*2.1 mm, 1.7 micron. Columnflow was 0.55 ml/min and mobile phase are used (A) 2 mM Ammonium Acetatein 0.1% Formic Acid in Water and (B) 0.1% Formic Acid in Acetonitrile.

For basic FCMS data: FCMS was recorded on an Agilent 1200 Series FC/MSDor Shimadzu FCMS 2020 equipped with electro-spray ionization andquadruple MS detector [ES+ve to give MH⁺] and equipped with Xbridge C18,2.1×50 mm columns packed with 5 mm C18-coated silica or Kinetex EVO C182.1×30 mm columns packed with 5 mm C18-coated silica, eluting with 0.05vol % NH₃.H₂O in water (solvent A) and acetonitrile (solvent B).

HPFC Analytical Method: HPFC was carried out on X Bridge C18 150*4.6 mm,5 micron. Column flow is 1.0 ml/min and mobile phase are used (A) 0.1%Ammonia in water and (B) 0.1% Ammonia in Acetonitrile.

Prep HPFC Analytical Method: The compound was purified on ShimadzuFC-20AP and UV detector. The column used was X-BRIDGE C18 (250*19)mm,5μ. Column flow was 16.0 ml/min. Mobile phase used was (A) 0.1% FormicAcid in Water and (B) Acetonitrile. Basic method used was (A) 5 mMammonium bicarbonate and 0.1% NH₃ in Water and (B) Acetonitrile or (A)0.1% Ammonium Hydroxide in Water and (B) Acetonitrile. The UV spectrawere recorded at 202 nm & 254 nm.

NMR Method: The 1H NMR spectra were recorded on a Bruker Ultra ShieldAdvance 400 MHz/5 mm Probe (BBFO). The chemical shifts are reported inpart-per-million.

As depicted in the Examples below, in certain exemplary embodiments,compounds are prepared according to the following general procedures. Itwill be appreciated that, although the general methods depict thesynthesis of certain compounds of the present invention, the followinggeneral methods, and other methods known to one of ordinary skill in theart, can be applied to all compounds and subclasses and species of eachof these compounds, as described herein.

Intermediates [1-[(4-Methoxyphenyl) methyl]-2,6-dioxo-3-piperidyl]trifluoromethanesulfonate (Intermediate IQ)

Step 1—5-Oxotetrahydrofuran-2-carboxylic acid

To a solution of 2-aminopentanedioic acid (210 g, 1.43 mol, CAS#617-65-2) in H₂O (800 mL) and HCl (12 M, 210 mL) was added a solutionof NaNO₂ (147 g, 2.13 mol) in H₂O (400 mL) at −5° C. The mixture wasstirred at 15° C. for 12 hrs. On completion, the mixture wasconcentrated and then dissolved in EA (500 mL) and filtered and washedwith EA (3×100 mL). The filtrate and washed solution were dried overNa₂SO₄, filtered and concentrated in vacuo to give the title compound(200 g, crude) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 6.43 (s, 1H),5.02-4.95 (m, 1H), 2.67-2.38 (m, 4H)

Step 2—N-[(4-methoxyphenyl)methyl]-5-oxo-tetrahydrofuran-2-carboxamide

To 5-oxotetrahydrofuran-2-carboxylic acid (120 g, 922 mmol) was addedSOCl₂ (246 g, 2.07 mol) at 0° C. slowly. The mixture was stirred at 85°C. for 3 hrs, and then the mixture was stirred at 15° C. for 6 hrs. Themixture was concentrated in vacuo. The residue was dissolved in dry DCM(1 L) at 0° C. under N₂. After that a solution of Et₃N (187 g, 1.84 mol)and 4-methoxybenzylamine (101 g, 738 mmol) in DCM (400 mL) was added,then the mixture was stirred at 15° C. for 3 hrs. On completion, water(600 mL) was added and the mixture was extracted with DCM (3×300 mL).The combined organic phase was washed with 0.5 M HCl (500 mL), brine(500 mL), dried over with anhydrous sodium sulfate and filtered. Thefiltrate was concentrated in vacuo and the residue was purified by flashsilica gel chromatography (PE:EA=1:1) to give the title compound (138 g,60% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.22-7.20 (d,J=8.0, 1H), 6.89-6.87 (d, J=8.0, 1H), 4.90-4.86 (m, 1H), 4.47-4.4.36 (m,2H) 3.81 (s, 3H), 2.67-2.64 (m, 1H), 2.59-2.54 (m, 2H), 2.40-2.38 (m,1H); LC-MS (ESI⁺) m/z 212.0 (M+Na)⁺.

Step 3—3-Hydroxy-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione

A solution ofN-[(4-methoxyphenyl)methyl]-5-oxo-tetrahydrofuran-2-carboxamide (138 g,553 mmol) in anhydrous THF (1500 mL) was cooled to −78° C. Then, t-BuOK(62.7 g, 559 mmol) in a solution of anhydrous THF (1000 mL) was addeddropwise slowly at -78° C. under nitrogen atmosphere. The resultingreaction mixture was stirred at -40° C. for 1 hr. On completion, thereaction mixture was quenched with saturated NH₄Cl solution (100 mL).The mixture was extracted with ethyl acetate (3×1500 mL). The combinedorganic layer was washed with brine (300 mL), dried over anhydroussodium sulfate, filtered and the filtrate was concentrated in vacuo. Theresidue was purified by silica gel chromatography (PE:EA=1:1) to givethe title compound (128 g, 92% yield) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 7.39-7.32 (m, 2H), 6.89-6.81 (m, 2H), 4.91 (s, 2H), 4.17-4.11(m, 1H), 3.80 (s, 3H), 3.54 (s, 1H), 2.98-2.87 (m, 1H), 2.73-2.60 (m,1H), 2.26-2.20 (m, 1H), 1.80 (dq, J=4.8, 13.1 Hz, 1H).

Step 4—[1-[(4-Methoxyphenyl) methyl]-2,6-dioxo-3-piperidyl]trifluoromethanesulfonate

To a solution of 3-hydroxy-1-[(4-methoxyphenyl) methyl] piperidine-2,6-dione (43.0 g, 173 mmol) and pyridine (27.3 g, 345 mmol) in DCM (500mL) was added trifluoromethylsulfonyl trifluoromethanesulfonate (73.0 g,258 mmol) dropwise at 0° C. The mixture was stirred at −10° C. for 1.5hours under N₂. On completion, the mixture was concentrated in vacuo.The residue was purified by column chromatography on silica gel(PE:EA=20:1/8:1) to give the title compound (45.0 g, 68% yield) as lightyellow gum. ¹H NMR (400 MHz, CDCl₃) δ 7.36 (d, J=8.4 Hz, 2H), 6.85-6.82(m, 2H), 5.32-5.28 (m, 1H), 4.91 (s, 2H), 3.79 (s, 3H), 3.02-2.97 (m,1H), 2.79-2.74 (m, 1H), 2.41-2.35 (m, 2H).

3-(4-Bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(Intermediate HP)

Step 1—2-Bromo-N-methyl-6-nitro-aniline

To a solution of 1-bromo-2-fluoro-3-nitro-benzene (40.0 g, 181 mmol, CAS#58534-94-4) in THF (40 mL) was added MeNH₂ (2 M, 400 mL). The reactionmixture was stirred at 60° C. for 12 hours. On completion, the reactionmixture was poured into sat.NaHCO₃ (30 mL) and extracted with EA (3×200mL). The combined organic layers were washed with brine (2×200 mL),dried with anhydrous Na₂SO₄, filtered and concentrated in vacuo to givethe title compound (40.0 g, 95% yield) as red oil. LC-MS (ESI⁺) m/z230.9 (M+H)⁺.

Step 2—3-Bromo-N2-methyl-benzene-1,2-diamine

To a mixture of 2-bromo-N-methyl-6-nitro-aniline (23.0 g, 99.5 mmol) inEA (300 mL) and H₂O (10 mL) was added AcOH (100 mL). The mixture waswarmed to 50° C. Then Le (22.2 g, 398 mmol) was added to the reactionmixture and the mixture was heated to 80° C. about 4 hours. Oncompletion, the reaction mixture was filtered and concentrated in vacuo.The residue was diluted with water (100 mL) and extracted with EA (3×200mL). The combined organic layers was dried over Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (20.0 g, 99% yield) asred oil. ¹H NMR (400 MHz, DMSO-d₆) δ 6.73-6.70 (m, 1H), 6.68-6.60 (m,2H), 5.02 (s, 2H), 3.67 (s, 1H), 2.58 (s, 3H).

Step 3—4-Bromo-3-methyl-1H-benzimidazol-2-one

To a mixture of 3-bromo-N2-methyl-benzene-1,2-diamine (20.0 g, 99.4mmol) in ACN (300 mL) was added CDI (32.2 g, 198 mmol). The reactionmixture was stirred at 85° C. for 12 hours under N₂ atmosphere. Oncompletion, the reaction mixture was concentrated in vacuo. The reactionmixture was diluted with water (200 mL), where a solid precipitate wasformed, which was filtered off. The solid was washed with water (1 L)and dried in vacuo to give the title compound (20.0 g, 88% yield) aswhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.17 (s, 1H), 7.14 (dd, J=1.2,8.0 Hz, 1H), 7.00-6.95 (m, 1H), 6.93-6.87 (m, 1H), 3.55 (s, 3H).

Step 4:3-(4-Bromo-3-methyl-2-oxo-benzimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione

To a solution of 4-bromo-3-methyl-1H-benzimidazol-2-one (12.0 g, 52.8mmol) in THE (300 mL) was added t-BuOK (7.12 g, 63.4 mmol). The reactionmixture was stirred at 0° C. for 0.5 hr. Subsequently,[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]trifluoromethanesulfonate (20.1 g, 52.8 mmol, Intermediate IQ) in asolution of THE (100 mL) was added dropwise. The resulting reactionmixture was stirred at 20° C. for 0.5 hr under N₂. On completion, thereaction mixture was quenched with saturated NH₄Cl (100 mL), andextracted with ethyl acetate (200 mL). The combined organic layers werewashed with brine (2×100 mL), dried over anhydrous sodium sulfate,filtered, the filtrate was concentrated in vacuo. The crude product waspurified by reversed-phase HPLC (0.1% PA condition) to give the titlecompound (13.3 g, 55% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃)δ 7.38 (d, J=8.8 Hz, 2H), 7.22 (d, J=8.0 Hz, 1H), 6.84 (d, J=8.8 Hz,2H), 6.80 (t, J=8.0 Hz, 1H), 6.48-6.40 (d, J=8.0 Hz, 1H), 5.22 (dd,J=5.2, 12.8 Hz, 1H), 5.04-4.93 (m, 2H), 3.81 (s, 3H), 3.80 (s, 3H),3.12-2.98 (m, 1H), 2.93-2.77 (m, 1H), 2.62 (dq, J=4.4, 13.2 Hz, 1H),2.20-2.17 (m, 1H).

Step5—3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

A mixture of3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione(13.3 g, 29.0 mmol) in a mixed solvent of Tol. (80 mL) and methanesulfonic acid (40 mL) was degassed and purged with N₂ for 3 times, andthen the mixture was stirred at 120° C. for 2 hrs under N₂ atmosphere.On completion, the reaction mixture was concentrated in vacuo to removetoluene. The residue was added 200 mL of ice water, and then white solidprecipitate formed. The mixture was filtered and the filtered cake wascollected and dried over in vacuo to give the title compound (7.30 g,74% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.13 (s, 1H),7.25 (d, J=8.0 Hz, 1H), 7.17 (d, J=8.0 Hz, 1H), 7.05-6.93 (m, 1H), 5.41(dd, J=5.2, 12.8 Hz, 1H), 3.64 (s, 3H), 2.96-2.83 (m, 1H), 2.78-2.59 (m,2H), 2.08-2.00 (m, 1H).

3-(3-Methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate AZK)

Step 1—Tert-butyl4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate

To a solution of3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (9.00g, 26.6 mmol, Intermediate HP), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate(12.3 g, 39.9 mmol) and XPhos-Pd-G2 (2.09 g, 2.66 mmol) in dioxane (150mL) and H₂O (15 mL) was added K₃PO₄ (11.3 g, 53.2 mmol). The reactionmixture was stirred at 80° C. for 4 hours under N₂. On completion, thereaction mixture was filtered. The filtrate was dried with anhydrousNa₂SO₄ and filtered. The filtrate was concentrated in vacuo. The residuewas triturated with sat. NH₄Cl (2×50 mL), water (2×50 mL) and EA (2×50mL) and filtered. The solid was dried in vacuo to give the titlecompound (8.00 g, 68% yield) as an off-white solid. LC-MS (ESI⁺) m/z441.1 (M+H)⁺

Step 2—Tert-butyl4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidine-1-carboxylate

To a solution of tert-butyl4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylate(8.00 g, 18.2 mmol) in DMF (20 mL) and THF (60 mL) was added H₂, Pd/C(1.00 g, 10 wt %) and Pd(OH)₂ (1.00 g, 3.56 mmol, 50 wt %). The mixturewas degassed and purged with nitrogen 3 times, then degassed and purgedwith hydrogen 3 times. The mixture was stirred at 25° C. for 16 hrsunder hydrogen (15 psi) atmosphere. On completion, the reaction mixturewas filtered and the combined filtrates were concentrated in vacuo togive the title compound (5.60 g, 70% yield) as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ 11.10 (s, 1H), 7.06-6.92 (m, 3H), 5.38 (m, 1H),4.18-3.96 (m, 2H), 3.60 (s, 3H), 3.48-3.39 (m, 1H), 2.97-2.81 (m, 3H),2.76-2.61 (m, 2H), 2.05-1.94 (m, 1H), 1.81 (m, 2H), 1.65-1.50 (m, 2H),1.47-1.40 (m, 9H). LC-MS (ESI⁺) m/z 287.4 (387.3)⁺.

Step3—3-(3-Methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

To a solution of tert-butyl4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]piperidine-1-carboxylate(100 mg, 226 umol) in DCM (1 mL) was added HCl/dioxane (1 mL). Thereaction mixture was stirred at 25° C. for 0.5 hr. On completion, thereaction mixture was concentrated in vacuo to give the title compound(85.0 mg, 99% yield) as a yellow solid. LC-MS (ESI⁺) m/z 343.3 (M+H)⁺.

1R,4r)-4-((Benzyloxy)methyl)cyclohexanecarbonyl chloride (IntermediateBAU)

Step 1—(1R,4r)-Methyl 4-(hydroxymethyl)cyclohexanecarboxylate

To a solution of 4-methoxycarbonylcyclohexanecarboxylic acid (20.0 g,107 mmol, CAS #15177-67-0) in the THF (200 mL) was added Et₃N (21.7 g,215 mmol, 29.9 mL) and isopropyl carbonochloridate (19.7 g, 161 mmol,22.4 mL) at 0° C. The mixture was stirred at 25° C. for 1 hour. Then themixture was filtered and the LiBH₄ (11.7 g, 537 mmol) was added inportion at 0° C. The mixture was stirred at 25° C. for 4 hours. Oncompletion, the mixture was quenched by water (500 mL) and extractedwith EA (3×1000 mL). The organic layers were dried over Na₂SO₄, filteredand concentrated in vacuo. The residue was purified by columnchromatography to give the title compound (9.70 g, 52% yield) ascolorless oil. ¹H NMR (400 MHz, CDCl₃) δ 3.67 (s, 3H), 3.47 (d, J=6.0Hz, 2H), 2.26 (tt, J=3.6, 12.4 Hz, 1H), 2.06-1.99 (m, 2H), 1.88 (dd,J=3.2, 13.6 Hz, 2H), 1.56-1.39 (m, 3H), 1.07-0.93 (m, 2H).

Step 2—(1R,4r)-Methyl 4-((benzyloxy)methyl)cyclohexanecarboxylate

To a solution of methyl 4-(hydroxymethyl)cyclohexanecarboxylate (9.70 g,56.3 mmol) in the THF (100 mL) was added KOH (4.74 g, 84.5 mmol), TBAI(4.16 g, 11.3 mmol), KI (1.87 g, 11.3 mmol) and BnBr (14.5 g, 84.5 mmol,10.0 mL). The mixture was stirred at 25° C. for 12 hours. On completion,the reaction mixture was filtered and concentrated in vacuo. The residuewas purified by column chromatography to give the title compound (11.0g, 74% yield) as colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.39-7.27 (m,5H), 4.50 (s, 2H), 3.67 (s, 3H), 3.29 (d, J=6.4 Hz, 2H), 2.25 (tt,J=3.6, 12.4 Hz, 1H), 2.04-1.98 (m, 2H), 1.91 (brdd, 0.7=3.6, 13.6 Hz,2H), 1.71-1.61 (m, 1H), 1.45-1.42 (m, 2H), 1.08-0.94 (m, 2H).

Step 3—(1R,4r)-4-((benzyloxy)methyl)cyclohexanecarboxylic acid

To a solution of methyl 4-(benzyloxymethyl)cyclohexanecarboxylate (11.0g, 41.9 mmol) in the THF (100 mL), MeOH (20 mL) and H₂O (20 mL) wasadded LiOH (5.02 g, 210 mmol). The mixture was stirred at 25° C. for 12hours. On completion, the reaction mixture was concentrated in vacuo.The residue was diluted with water (100 mL) and washed with PE (200 mL).The water phase was acidified by HCl (aq, 1M) to pH=4. Then the mixturewas extracted with DCM (3×200 mL). The organic layer was dried overNa₂SO₄, filtered and concentrated in vacuo to give the title compound(10.1 g, 97% yield) as colorless oil. ¹H NMR (400 MHz, CDCl₃) δ7.41-7.26 (m, 5H), 4.50 (s, 2H), 3.30 (d, J=6.4 Hz, 2H), 2.28 (tt,0.7=3.6, 12.4 Hz, 1H), 2.05 (dd, J=2.8, 13.6 Hz, 2H), 1.92 (dd, J=2.8,13.6 Hz, 2H), 1.65-1.62 (m, 1H), 1.46 (dq, J=3.6, 12.8 Hz, 2H),1.11-0.95 (m, 2H).

Step 4—(1R,4r)-4-((Benzyloxy)methyl)cyclohexanecarbonyl chloride

To a solution of 4-(benzyloxymethyl)cyclohexanecarboxylic acid (10.0 g,40.3 mmol) in the DCM (100 mL) was added DMF (294 mg, 4.03 mmol) and(COCl)₂ (7.67 g, 60.4 mmol, 5.29 mL) in portion at 0° C. The mixture wasstirred at 0° C. for 2 hrs. On completion, the reaction mixture wasconcentrated in vacuo to give the title compound (10.7 g, 99% yield) asyellow oil.

Methyl 5-amino-2-bromo-4-iodo-benzoate (Intermediate BAV)

To a solution of methyl 3-amino-4-iodo-benzoate (5.00 g, 18.1 mmol, CAS#412947-54-7) in DMF (25 mL) was added NBS (3.28 g, 18.4 mmol). Themixture was stirred at 0° C. for 2 hours. On completion, the mixture waspoured into 500 mL water and a solid was obtained. The mixture wasfiltered then the filtered cake was washed with water (3×50 mL) anddried in vacuo to give the title compound (6.00 g, 93% yield) as yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.84 (s, 1H), 7.13 (s, 1H), 5.66 (brs, 2H), 3.81 (s, 3H).

Methyl6-bromo-2-[4-(hydroxymethyl)cyclohexyl]-1,3-benzothiazole-5-carboxylate(Intermediate BAW)

Step 1—Methyl5-[[4-(benzyloxymethyl)cyclohexanecarbonyl]amino]-2-bromo-4-iodo-benzoate

To a solution of methyl 5-amino-2-bromo-4-iodo-benzoate (707 mg, 1.9mmol, Intermediate BAV) in DCM (10 mL) was added Et₃N (603 mg, 5.96mmol). Then a mixture of 4-(benzyloxymethyl)cyclohexane carbonylchloride (530 mg, 1.99 mmol, Intermediate BAU) in DCM (20 mL) was addedto the reaction mixture. The mixture was stirred at 0° C. for 2 hours.On completion, the mixture was concentrated in vacuo. The residue wasdiluted with water (50 mL) and extracted with EA (3×100 mL). Thecombined organic layers were washed with brine (50 mL), dried overNa₂SO₄, filtered and concentrated of most solvent. Then the solid wasprecipitated out, then filtered, the cake was dried in vacuo to give thetitle compound (660 mg, 56% yield) as white solid. ¹H NMR (400 MHz,CDCl₃) δ 8.76 (d, J=1.6 Hz, 1H), 8.09 (d, J=1.6 Hz, 1H), 7.52 (s, 1H),7.41-7.27 (m, 5H), 4.52 (d, J=1.6 Hz, 2H), 3.92 (d, J=1.6 Hz, 3H), 3.34(dd, J=1.6, 6.0 Hz, 2H), 2.35-2.24 (m, 1H), 2.12 (d, J=13.2 Hz, 2H),2.00 (d, J=13.2 Hz, 2H), 1.77-1.58 (m, 3H), 1.19-1.05 (m, 2H).

Step2—2-[4-(Benzyloxymethyl)cyclohexyl]-6-bromo-1,3-benzothiazole-5-carboxylicacid

To a solution of methyl5-[[4-(benzyloxymethyl)cyclohexanecarbonyl]amino]-2-bromo-4-iodo-benzoate(5.60 g, 9.55 mmol) in DMF (50 mL) was added CuI (363 mg, 1.91 mmol) andNa₂S.9H₂O (13.7 g, 57.3 mmol). The mixture was stirred at 80° C. for 6hours, and then cooled to rt. Then TFA (15.4 g, 135 mmol) was added tothe mixture and the mixture was stirred at 25° C. for 6 hours. Oncompletion, the residue was diluted with water (100 mL) and extractedwith EA (3×100 mL). The combined organic layers were washed with brine(100 mL), dried over Na₂SO₄, filtered and concentrated in vacuo to givethe title compound (4.00 g, 56% yield) as yellow oil. LC-MS (ESI+) m/z462.1 (M+3)⁺.

Step 3 Methyl2-[4-(benzyloxymethyl)cyclohexyl]-6-bromo-1,3-benzothiazole-5-carboxylate

To a solution of2-[4-(benzyloxymethyl)cyclohexyl]-6-bromo-1,3-benzothiazole-5-carboxylicacid (4.00 g, 8.69 mmol) in DMF (20 mL) was added CH₃I (2.47 g, 17.3mmol) and K₂CO₃ (2.40 g, 17.3 mmol). The mixture was stirred at 15° C.for 2 hours. On completion, the mixture was filtered and concentrated invacuo. The residue was purified by flash silica gel chromatography(PE:EA 3:1) to give title compound (3.00 g, 72% yield) as white solid.¹H NMR (400 MHz, CDCl₃) δ 8.31 (s, 1H), 8.05 (s, 1H), 7.31-7.21 (m, 5H),4.44 (s, 2H), 3.88 (s, 3H), 3.27 (d, J=6.0 Hz, 2H), 2.97 (t, J=12.0 Hz,1H), 2.87 (s, 5H), 2.80 (s, 5H), 2.19 (d, J=12.4 Hz, 2H), 1.95 (d,J=13.6 Hz, 2H), 1.73-1.65 (m, 1H), 1.58 (q, J=12.8 Hz, 2H), 1.20-1.07(m, 2H).

Step 4—Methyl6-bromo-2-[4-(hydroxymethyl)cyclohexyl]-1,3-benzothiazole-5-carboxylate

To a solution of methyl2-[4-(benzyloxymethyl)cyclohexyl]-6-bromo-1,3-benzothiazole-5-carboxylate(2.00 g, 4.22 mmol) in DCM (40 mL) was added BCl₃ (9.88 g, 84.3 mmol).The mixture was stirred at 25° C. for 2 hours. On completion, to themixture was added sat.NaHCO₃. aq (50 mL) then extracted with DCM (3×50mL). The combined organic layers were washed with brine (100 mL), driedover Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound (1.60 g, 90% yield) as white solid. ¹H NMR (400 MHz, CDCl₃) δ8.48 (s, 1H), 8.21-8.13 (m, 1H), 3.98 (s, 3H), 3.55 (d, J=6.0 Hz, 2H),3.25-3.12 (m, 1H), 2.42-2.26 (m, 2H), 2.09-1.98 (m, 2H), 1.78-1.62 (m,3H), 1.29-1.16 (m, 2H).

6-(Trifluoromethyl)pyridine-2-carboxamide (Intermediate ATI)

Step 1—6-(Trifluoromethyl)pyridine-2-carbonyl chloride

To a mixture of 6-(trifluoromethyl)pyridine-2-carboxylic acid (21.0 g,109 mmol, CAS #131747-42-7) and DMF (401 mg, 5.49 mmol) in DCM (300 mL)was added (COCl)₂ (27.9 g, 219 mmol) at 0° C. The mixture was stirred at25° C. for 1 hour. On completion, the reaction mixture was concentratedin vacuo to give the title compound (22 g, 95% yield) as light yellowoil.

Step 2—6-(Trifluoromethyl)pyridine-2-carboxamide

A solution of 6-(trifluoromethyl)pyridine-2-carbonyl chloride (21.5 g,102 mmol) in THF (100 mL) was added NFL FLO (143 g, 1.03 mol, 158 mL,25% solution) at 0° C. The mixture was stirred at 25° C. for 1 hour. Oncompletion, the reaction mixture was concentrated in vacuo to remove THFand then filtered to give the filter cake as title product (19 g, 90%yield) as light yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.35-8.24 (m,2H), 8.08 (dd, J=1.6, 6.8 Hz, 1H), 8.05-7.78 (m, 2H); LC-MS (ESI⁺) m/z191.0 (M+H)+.

N-[2-(4-formylcyclohexyl)-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide(Intermediate BAX)

Step 1—Methyl2-[4-(hydroxymethyl)cyclohexyl]-6-[[6-(trifluoromethyl)pyridine-2-carbonyl]amino]-1,3-benzothiazole-5-carboxylate

To a solution of methyl6-bromo-2-[4-(hydroxymethyl)cyclohexyl]-1,3-benzothiazole-5-carboxylate(300 mg, 780 umol, Intermediate BAW) and6-(trifluoromethyl)pyridine-2-carboxamide (163 mg, 858 umol,Intermediate ATI) in dioxane (30 mL) was added Xantphos (90.3 mg, 156umol), Cs₂CO₃ (763 mg, 2.34 mmol) and Pd₂(dba)₃ (71.4 mg, 78.1 umol) at25° C. The mixture was stirred at 80° C. for 12 hrs under N₂. Oncompletion, the mixture was filtered with celite and concentrated invacuo. The residue was purified by column chromatography to give titlecompound (120 mg, 31% yield) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆)δ 12.82 (s, 1H), 9.44 (s, 1H), 8.54 (s, 1H), 8.50-8.46 (m, 1H),8.45-8.38 (m, 1H), 8.23 (d, J=7.8 Hz, 1H), 4.53-4.40 (m, 1H), 3.98 (s,3H), 3.27 (t, J=5.6 Hz, 2H), 3.08 (s, 1H), 2.19 (d, J=13.0 Hz, 2H),1.93-1.83 (m, 2H), 1.66-1.51 (m, 2H), 1.48-1.38 (m, 1H), 1.18-1.05 (m,2H).

Step2—N-[2-[4-(hydroxymethyl)cyclohexyl]-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

To a solution of methyl2-[4-(hydroxymethyl)cyclohexyl]-6-[[6-(trifluoromethyl)pyridine-2-carbonyl]amino]-1,3-benzothiazole-5-carboxylate (120 mg, 243 umol) in THF (10 mL)was added MeMgBr (3 M, 405 uL). The mixture was stirred at 0° C. for 2hours. The reaction mixture was quenched by addition sat. NH₄Cl (10 mL)at 0° C., and then diluted with water (50 mL) and extracted with EA(3×50 mL). The combined organic layers were washed with brine (100 mL),dried over Na₂SO₄, filtered and concentrated in vacuo to give a residue.The residue was purified by prep-HPLC (column: Phenomenex Synergi C18150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B %: 44%-74%, 10min) to give the title compound (80.0 mg, 60% yield) as white solid. ¹HNMR (400 MHz, DMSO-d₆) δ 12.56 (s, 1H), 9.07 (s, 1H), 8.51-8.45 (m, 1H),8.39 (t, J=8.0 Hz, 1H), 8.20 (d, J=7.6 Hz, 1H), 7.94-7.88 (m, 1H), 6.08(s, 1H), 4.46 (t, J=5.2 Hz, 1H), 3.28 (t, J=5.6 Hz, 2H), 3.10-3.00 (m,1H), 2.19 (d, J=11.2 Hz, 2H), 1.94-1.84 (m, 2H), 1.64 (s, 6H), 1.61-1.53(m, 2H), 1.50-1.40 (m, 1H), 1.19-1.06 (m, 2H).

Step3—N-[2-(4-formylcyclohexyl)-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

To a solution ofN-[2-[4-(hydroxymethyl)cyclohexyl]-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (50.0 mg, 101 umol) inDCM (10 mL) was added DMP (51.5 mg, 121 umol). The mixture was stirredat 25° C. for 2 hours. On completion, the mixture was added 10 mL sat.NaHCO₃ and 10 mL sat. Na₂S₂O₃, then extracted with DCM (3×50 mL). Thecombined organic layers were washed with brine (100 mL), dried overNa₂SO₄, filtered and concentrated in vacuo to give the title compound(60.0 mg, 90% yield) as yellow solid. LC-MS (ESI⁺) m/z 492.2 (M+1)⁺.

3-(4-amino-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione(Intermediate BAP)

Step 1—2-(Methylamino)-3-nitro-benzoic acid

To a solution of MeNH₂/EtOH (54.0 mmol, 200 mL, 30% solution) was added2-fluoro-3-nitro-benzoic acid (10.0 g, 54.0 mmol) in portions at 0° C.Then the reaction mixture was stirred at 20° C. for 2 hrs. Oncompletion, the mixture was concentrated in vacuo. The residue wasdiluted with water (100 mL), acidified with citric acid to pH=3-5,stirred and filtered. The filter cake was dried in vacuo to give thetitle compound (9.60 g, 91% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 13.41 (s, 1H), 8.62 (s, 1H), 8.04 (dd, J=1.6, 8.0 Hz, 1H),7.97 (dd, J=1.6, 8.0 Hz, 1H), 6.72 (t, J=8.0 Hz, 1H), 2.70 (s, 3H).

Step 2—3-Methyl-4-nitro-1H-benzimidazol-2-one

To a solution of 2-(methylamino)-3-nitro-benzoic acid (8.60 g, 43.8mmol) and DIPEA (17.0 g, 132 mmol) in t-BuOH (200 mL) was added DPPA(12.1 g, 43.8 mmol) dropwise at 0° C. Then the reaction mixture wasstirred at 85° C. for 12 hours. On completion, the mixture was dilutedwith MeOH (100 mL), cooled to 10-20° C., filtered and the filter cakewas dried in vacuo to give the title compound (6.80 g, 80% yield) as ayellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.61 (s, 1H), 7.58 (dd,J=0.8, 8.0 Hz, 1H), 7.30 (dd, J=0.8, 8.0 Hz, 1H), 7.18-7.07 (m, 1H),3.34 (s, 3H).

Step3—1-[(4-Methoxyphenyl)methyl]-3-(3-methyl-4-nitro-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione

To a solution of 3-methyl-4-nitro-1H-benzimidazol-2-one (7.20 g, 37.3mmol) in THE (70 mL) was added t-BuOK (8.37 g, 74.6 mmol) at −10-0° C.One hour later, a solution of[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]trifluoromethanesulfonate (21.3 g, 55.9 mmol, Intermediate IQ) in THE(50 mL) was added into the above mixture and the reaction mixture wasstirred at 0-20° C. for 12 hrs. On completion, the mixture was acidifiedwith PA to pH=3-5, diluted with water (300 mL), and extracted with EA(2×300 mL). The organic layer was washed with brine (200 mL), thenconcentrated in vacuo. The residue was purified by reverse phase (0.1%PA condition) to give the title compound (5.80 g, 37% yield) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.69 (dd, J=0.8, 8.0 Hz, 1H), 7.46(d, J=8.0 Hz, 1H), 7.27-7.17 (m, 3H), 6.93-6.78 (m, 2H), 5.67 (dd,J=5.2, 12.8 Hz, 1H), 4.94-4.62 (m, 2H), 3.72 (s, 3H), 3.41 (s, 3H),3.11-2.98 (m, 1H), 2.89-2.70 (m, 2H), 2.17-2.08 (m, 1H).

Step 4—3-(3-Methyl-4-nitro-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione

To a solution of1-[(4-methoxyphenyl)methyl]-3-(3-methyl-4-nitro-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (2.00 g, 4.71 mmol) in TFA (20 mL) was added TfOH(2 mL). The reaction mixture was stirred at 60° C. for 12 hours. Oncompletion, the mixture was concentrated in vacuo. The residue waspurified by reverse phase (0.1% FA condition) to give the title compound(900 mg, 63% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.19(s, 1H), 7.68 (dd, J=0.8, 8.0 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.23 (t,J=8.0 Hz, 1H), 5.51 (dd, J=5.2, 12.8 Hz, 1H), 3.41 (s, 3H), 2.95-2.85(m, 1H), 2.80-2.60 (m, 2H), 2.13-2.06 (m, 1H).

Step 5—3-(4-Amino-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione

To a solution of3-(3-methyl-4-nitro-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (850mg, 2.79 mmol) in THF (50 mL) was added Pd/C (200 mg, 10% wt). Thereaction mixture was stirred at 20° C. for 12 hrs under H₂ (15 Psi)atmosphere. On completion, the mixture was filtered and the filtrate wasconcentrated in vacuo to give the title compound (0.70 g, 91% yield) asa pink solid. LC-MS (ESI⁺) m/z 275.1 (M+H)⁺.

3-(4-(7-Azaspiro[3.5]nonan-2-ylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate BBD)

Step 1-Tert-butyl2-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]amino]-7-azaspiro[3.5]nonane-7-carboxylate

To a mixture of3-(4-amino-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (200mg, 729 umol, Intermediate BAP) and tert-butyl2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (174 mg, 729 umol, CAS #203661-69-2) in dioxane (2 mL) was and tetraethoxytitanium (499 mg, 2.19mmol). The reaction mixture stirred at 80° C. for 17 hrs. Then themixture was cooled to 25° C. Then NaBH₃CN (137 mg, 2.19 mmol) was addedto the reaction mixture and the mixture was stirred at 25° C. for 3 hrs.On completion, the reaction mixture was filtered and the filtrate wasconcentrated in vacuo. The crude product was purified by reverse phaseflash (0.1% FA condition) to give the title compound (100 mg, 27% yield)as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.07 (s, 1H), 6.85 (dd,J=7.6, 8.0 Hz, 1H), 6.53 (d, J=7.6 Hz, 1H), 6.30 (d, J=8.0 Hz, 1H), 5.29(dd, J=5.2, 12.8 Hz, 1H), 5.21 (d, J=6.8 Hz, 1H), 3.91-3.75 (m, 1H),3.62 (s, 3H), 3.31-3.26 (m, 2H), 3.22 (s, 2H), 2.93-2.83 (m, 1H),2.71-2.59 (m, 2H), 2.32-2.28 (m, 2H), 2.02-1.93 (m, 1H), 1.73-1.66 (m,2H), 1.56-1.54 (m, 2H), 1.51-1.48 (m, 2H), 1.40 (s, 9H); LC-MS (ESI⁺)m/z 498.3 (M+H)⁺.

Step2—3-(4-(7-Azaspiro[3.5]nonan-2-ylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

A solution of tert-butyl2-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]amino]-7-azaspiro[3.5]nonane-7-carboxylate (40.0 mg, 80.4 umol) and HCl/dioxane(4 M, 1 mL) in DCM (1 mL) was stirred at 25° C. for 1 hour. Oncompletion, the reaction mixture was concentrated in vacuo to give thetitle compound (32.0 mg, 92% yield) as brown gum. LC-MS (ESI⁺) m/z 398.2(M+H)⁺.

6-(1,1-Difluoroethyl)picolinamide (Intermediate BAD)

Step 1—6-(1,1-Difluoroethyl)picolinic acid

To a solution of methyl 6-(l, 1-difluoroethyl)pyridine-2-carboxylate(27.0 g, 134 mmol, CAS #1211529-86-0) in methanol (40 mL) and THF (80mL) was added a solution of LiOH.H₂O (11.2 g, 268 mmol) in H₂O (20 mL).The mixture was stirred at 25° C. for 2 hours. On completion, thereaction mixture was concentrated in vacuo. The residue was acidifiedwith 4 N aq.HCl till pH=3. The precipitated solid was filtered,collected and dried to give the title compound (22.0 g, 86% yield) as anoff-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 14.26-12.46 (m, 1H),8.22-8.10 (m, 2H), 7.96-7.86 (m, 1H), 2.03 (t, J=19.2 Hz, 3H).

Step 2—6-(1,1-Difluoroethyl)picolinoyl chloride

To a solution of 6-(1,1-difluoroethyl)pyridine-2-carboxylic acid (22.0g, 117 mmol) in DCM (220 mL) and DMF (859 mg, 11.76 mmol) was added(COCl)₂ (29.8 g, 235.11 mmol) dropwise at 0° C. The mixture was stirredat 25° C. for 0.5 hour. On completion, the reaction mixture wasconcentrated in vacuo to give the title compound (24.0 g, 100% yield) asa yellow solid.

Step 3—6-(1,1-Difluoroethyl)picolinamide

A solution of 6-(1,1-difluoroethyl)pyridine-2-carbonyl chloride (24.0 g,116 mmol) in THF (100 mL) was added to NFL FLO (146 g, 1.17 mol, 28%solution) dropwise at 0° C. The mixture was stirred at 25° C. for 0.5hour. On completion, the residue was diluted with FLO (100 mL) andextracted with EA (3×200 mL). The combined organic layers were washedwith brine (100 mL), dried over Na₂SO₄, filtered and concentrated invacuo to give the title compound (18.0 g, 81% yield) as an off-whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.26-8.10 (m, 3H), 7.90 (s, 1H), 7.78(s, 1H), 2.12 (t, J=19.2 Hz, 3H).

4-Bromo-2-iodo-5-methoxyaniline (Intermediate BCT)

Step 1—2-Iodo-5-methoxyaniline

To a solution of 1-iodo-4-methoxy-2-nitro-benzene (12.5 g, 44.8 mmol,CAS #58755-70-7) in the EtOH (200 mL) and H₂O (40 mL) was added NH₄Cl(24.0 g, 448 mmol) and Fe (15.0 g, 269 mmol). The mixture was refluxedat 80° C. for 3 hrs. On completion, the reaction mixture was filteredand concentrated in vacuo. The residue was purified by columnchromatography to give the title compound (10.5 g, 94% yield) as yellowsolid. ¹H NMR (400 MHz, CDCl₃) δ 7.49 (d, J=8.6 Hz, 1H), 6.34 (d, J=2.8Hz, 1H), 6.14 (dd, J=2.8, 8.4 Hz, 1H), 4.08 (s, 2H), 3.75 (s, 3H).

Step 2—4-Bromo-2-iodo-5-methoxyaniline

To a solution of 2-iodo-5-methoxy-aniline (5.00 g, 20.1 mmol) in the DCM(100 mL) was added NBS (3.57 g, 20.1 mmol). The mixture was stirred at25° C. for 1 hr. On completion, the reaction mixture was concentrated invacuo and the residue was purified by column chromatography (SiO₂,PE:EA=10:1 to 5:1) to give the title compound (6.30 g, 96% yield) asyellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.70 (s, 1H), 6.33 (s, 1H), 4.13(s, 2H), 3.83 (s, 3H).

(1R,4r)-Methyl 4-(chlorocarbonyl)cyclohexanecarboxylate (IntermediateBCU)

To a solution of 4-methoxycarbonylcyclohexanecarboxylic acid (500 mg,2.69 mmol) in the DCM (10 mL) was added DMF (19.6 mg, 268 umol, 20.6 uL)and (COCl)₂ (511 mg, 4.03 mmol). The mixture was stirred at 25° C. for 1hr. On completion, the reaction mixture was concentrated in vacuo togive the title compound (549 mg, 99% yield) as yellow oil.

Methyl 4-(6-bromo-5-methoxy-1,3-benzothiazol-2-yl)cyclohexanecarboxylate(Intermediate BFN)

Step 1: (1r,4r)-Methyl4-((4-bromo-2-iodo-5-methoxyphenyl)carbamoyl)cyclohexanecarboxylate

To a solution of 4-bromo-2-iodo-5-methoxy-aniline (880 mg, 2.68 mmol,Intermediate BCT) and Et3N (814 mg, 8.05 mmol) in the DCM (10 mL) wasadded methyl 4-chlorocarbonylcyclohexanecarboxylate (549 mg, 2.68 mmol,Intermediate BCU). The mixture was stirred at 25° C. for 12 hrs. Oncompletion, the reaction mixture was washed with water (50 mL). Theorganic layer was dried over Na2SO4, filtered and concentrated in vacuoand the residue was triturated with (PE:EA=3:1) to give the titlecompound (800 mg, 60% yield) as white solid. 1H NMR (400 MHz, CDCl₃) δ8.15 (s, 1H), 7.86 (s, 1H), 7.52 (s, 1H), 3.91 (s, 3H), 3.70 (s, 3H),2.41-2.27 (m, 2H), 2.15 (d, J=12.6 Hz, 4H), 1.69-1.49 (m, 4H).

Step2—(1R,4r)-4-(6-Bromo-5-hydroxybenzo[d]thiazol-2-yl)cyclohexanecarboxylicacid

To a solution of methyl4-[(4-bromo-2-iodo-5-methoxy-phenyl)carbamoyl]cyclohexanecarboxylate(0.8 g, 1.61 mmol) in the DMF (10 mL) was added Na₂S.9H₂O (774 mg, 3.22mmol) and CuI (61.4 mg, 322 umol). The mixture was stirred at 80° C. for12 hrs under N₂. Then the mixture was cooled down to room temperatureand HCl (12 M, 1.34 mL, 36% solution) was added. The mixture was stirredat 25° C. for 5 hrs. On completion, the reaction mixture was dilutedwith EA (100 mL) and washed with water (3×100 mL). The organic layer wasdried over Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound (570 mg, 99% yield) as yellow solid. LC-MS (ESI⁺) m/z 370.2(M+H)+.

Step 3—(1R,4r)-Methyl4-(6-bromo-5-methoxybenzo[d]thiazol-2-yl)cyclohexanecarboxylate

To a solution of4-(6-bromo-5-hydroxy-1,3-benzothiazol-2-yl)cyclohexanecarboxylic acid(567 mg, 1.59 mmol) in the DMF (10 mL) was added K₂CO₃ (440 mg, 3.19mmol) and Mel (678 mg, 4.78 mmol). The mixture was stirred at 25° C. for3 hrs. On completion, the reaction mixture was diluted with EA (100 mL)and washed with water (3×100 mL). The organic layer was dried overNa₂SO₄, filtered and concentrated in vacuo and purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=10/1 to 5/1) to givethe title compound (320 mg, 47% yield) as white solid. ¹H NMR (400 MHz,CDCl₃) δ 8.00 (s, 1H), 7.49 (s, 1H), 3.97 (s, 3H), 3.71 (s, 3H),3.10-3.01 (m, 1H), 2.34-2.30 (m, 2H), 2.21-2.16 (m, 2H), 2.15-2.10 (m,1H), 1.75-1.61 (m, 4H).

6-(1,1-Difluoroethyl)-N-(2-((1r,4r)-4-formylcyclohexyl)-5-methoxybenzo[d]thiazol-6-yl)picolinamide (Intermediate BCV)

Step 1—(1R,4r)-Methyl4-(6-(6-(1,1-difluoroethyl)picolinamido)-5-methoxybenzo[d]thiazol-2-yl)cyclohexanecarboxylate

To a solution of methyl4-(6-bromo-5-methoxy-1,3-benzothiazol-2-yl)cyclohexanecarboxylate (380mg, 988 umol, Intermediate BFN) and6-(1,1-difluoroethyl)pyridine-2-carboxamide (193 mg, 1.04 mmol,Intermediate BAD) in dioxane (4 mL) was added Pd₂(dba)₃ (90.5 mg, 98.8umol), Xantphos (114 mg, 197 umol) and Cs₂CO₃ (644 mg, 1.98 mmol). Themixture was stirred at 100° C. for 6 hrs under N₂. On completion, themixture was concentrated in vacuo. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=10/1 to 5/1) to givethe title compound (415 mg, 86% yield) as white solid. ¹H NMR (400 MHz,CDCl₃) δ 10.78 (s, 1H), 9.13 (s, 1H), 8.38 (d, J=7.2 Hz, 1H), 8.07 (t,J=7.6 Hz, 1H), 7.88 (dd, J=0.8, 7.6 Hz, 1H), 7.53 (s, 1H), 4.04 (s, 3H),3.71 (s, 3H), 3.12-3.02 (m, 1H), 2.47-2.39 (m, 1H), 2.37-2.30 (m, 2H),2.23-2.12 (m, 2H), 1.77-1.64 (m, 4H).

Step2—6-(1,1-Difluoroethyl)-N-(2-((1r,4r)-4-(hydroxymethyl)cyclohexyl)-5-methoxybenzo[d]thiazol-6-yl)picolinamide

To a solution of methyl4-[6-[[6-(1,1-difluoroethyl)pyridine-2-carbonyl]amino]-5-methoxy-1,3-benzothiazol-2-yl]cyclohexanecarboxylate(100 mg, 204 umol) in the THF (2 mL) was added LiAlH₄ (15.5 mg, 408umol) at −40° C. and the mixture was stirred at −40° C. for 1 hr. Oncompletion, the reaction mixture was quenched by water (0.1 mL) and NaOH(15% aq, 0.1 mL) at 0° C. Then the mixture was dried over Na₂SO₄,filtered and concentrated in vacuo to give the title compound (94 mg,99% yield) as yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 10.78 (s, 1H),9.13 (s, 1H), 8.38 (d, J=7.6 Hz, 1H), 8.07 (t, J=7.6 Hz, 1H), 7.88 (d,J=7.6 Hz, 1H), 7.54 (s, 1H), 4.05 (s, 3H), 3.55 (d, J=6.4 Hz, 2H),3.10-3.00 (m, 1H), 2.36-2.27 (m, 2H), 2.18 (t, J=18.4 Hz, 3H), 2.04-1.96(m, 2H), 1.76-1.64 (m, 3H), 1.26-1.14 (m, 2H).

Step3—6-(1,1-Difluoroethyl)-N-(2-((1r,4r)-4-formylcyclohexyl)-5-methoxybenzo[d]thiazol-6-yl)picolinamide

To a solution of6-(1,1-difluoroethyl)-N-[2-[4-(hydroxymethyl)cyclohexyl]-5-methoxy-1,3-benzothiazol-6-yl]pyridine-2-carboxamide(94.0 mg, 203 umol) in the DCM (1 mL) was added DMP (95.0 mg, 224 umol).The mixture was stirred at 25° C. for 1 hr. On completion, the reactionmixture was quenched by the addition of Na₂S₂O₃ (aq. 3 mL) and NaHCO₃(aq. 3 mL). Then the mixture was extracted with DCM (2×20 mL). Theorganic layer was dried over Na₂SO₄, filtered and concentrated in vacuoto give the title compound (90 mg, 96% yield) as yellow solid. LC-MS(ESI⁺) m/z 460.2 (M+H)⁺.

6-(Trifluoromethyl)pyridine-2-carboxamide (Intermediate ATI)

Step 1—6-(Trifluoromethyl)pyridine-2-carbonyl chloride

To a mixture of 6-(trifluoromethyl)pyridine-2-carboxylic acid (21.0 g,109 mmol, CAS #131747-42-7) and DMF (401 mg, 5.49 mmol) in DCM (300 mL)was added (COCl)₂ (27.9 g, 219 mmol) at 0° C. The mixture was stirred at25° C. for 1 hour. On completion, the reaction mixture was concentratedin vacuo to give the title compound (22 g, 95% yield) as light yellowoil.

Step 2—6-(Trifluoromethyl)pyridine-2-carboxamide

A solution of 6-(trifluoromethyl)pyridine-2-carbonyl chloride (21.5 g,102 mmol) in THF (100 mL) was added NH₃H₂O (143 g, 1.03 mol, 158 mL, 25%solution) at 0° C. The mixture was stirred at 25° C. for 1 hour. Oncompletion, the reaction mixture was concentrated in vacuo to remove THFand then filtered to give the filter cake as title product (19 g, 90%yield) as light yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.35-8.24 (m,2H), 8.08 (dd, J=1.6, 6.8 Hz, 1H), 8.05-7.78 (m, 2H); LC-MS (ESI⁺) m/z191.0 (M+H)⁺.

N-[2-(4-formylcyclohexyl)-5-methoxy-1,3-benzothiazol-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide(Intermediate BCN)

Step 1—(1R,4r)-Methyl4-(5-methoxy-6-(6-(trifluoromethyl)picolinamido)benzo[d]thiazol-2-yl)cyclohexanecarboxylate

To a solution of methyl4-(6-bromo-5-methoxy-1,3-benzothiazol-2-yl)cyclohexanecarboxylate (300mg, 780 umol, Intermediate BFN) and6-(trifluoromethyl)pyridine-2-carboxamide (163 mg, 858 umol,Intermediate ATI) in the dioxane (3 mL) was added Pd₂(dba)₃ (71.4 mg,78.0 umol), Xantphos (90.3 mg, 156 umol) and Cs₂CO₃ (508 mg, 1.56 mmol).The mixture was stirred at 100° C. for 6 hrs under N₂. On completion,the mixture was concentrated in vacuo. The residue was purified bycolumn chromatography (SiO₂, Petroleum ether/Ethyl acetate=10/1 to 3/1)to give the title compound (300 mg, 74% yield) as white solid. ¹H NMR(400 MHz, CDCl₃) δ 10.70 (s, 1H), 9.12 (s, 1H), 8.51 (d, J=8.0 Hz, 1H),8.14 (t, J=8.0 Hz, 1H), 7.89 (d, J=7.6 Hz, 1H), 7.54 (s, 1H), 4.06 (s,3H), 3.72 (s, 3H), 3.10-3.06 (m, 1H), 2.47-2.39 (m, 1H), 2.34 (d, J=11.2Hz, 2H), 2.19 (d, J=11.2 Hz, 2H), 1.78-1.59 (m, 4H).

Step2—N-(2-((1r,4r)-4-(hydroxymethyl)cyclohexyl)-5-methoxybenzo[d]thiazol-6-yl)-6-(trifluoromethyl)picolinamide

To a solution of methyl4-[5-methoxy-6-[[6-(trifluoromethyl)pyridine-2-carbonyl]amino]-1,3-benzothiazol-2-yl]cyclohexanecarboxylate(50.0 mg, 101 umol) in the THF (1 mL) was added LiAlH₄ (3.85 mg, 101umol) under 0° C. The mixture was stirred at 0° C. for 1 hr. Oncompletion, the reaction mixture was quenched by water (0.05 mL) andNaOH (15% aq, 0.05 mL) at 0° C. Then the mixture was dried over Na₂SO₄,filtered and concentrated in vacuo to give the title compound (47.0 mg,99% yield) as yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 10.70 (s, 1H),9.11 (s, 1H), 8.51 (d, J=7.6 Hz, 1H), 8.14 (t, J=7.6 Hz, 1H), 7.89 (d,J=7.6 Hz, 1H), 7.54 (s, 1H), 4.06 (s, 3H), 3.55 (t, J=6.0 Hz, 2H),3.08-3.02 (m, 1H), 2.36-2.29 (m, 2H), 2.01 (dd, J=3.2, 13.2 Hz, 2H),1.77-1.66 (m, 2H), 1.65-1.58 (m, 1H), 1.33 (t, J=5.6 Hz, 1H), 1.25-1.14(m, 2H).

Step3—N-(2-((1r,4r)-4-formylcyclohexyl)-5-methoxybenzo[d]thiazol-6-yl)-6-(trifluoromethyl)picolinamide

To a solution ofN-[2-[4-(hydroxymethyl)cyclohexyl]-5-methoxy-1,3-benzothiazol-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (47.0 mg, 100 umol) in the DCM (1 mL) wasadded DMP (51.4 mg, 121 umol). The mixture was stirred at 25° C. for 1hour. On completion, the reaction mixture was quenched by the additionof Na₂S₂O₃ (aq. 3 mL) and NaHCO₃ (aq. 3 mL). Then the mixture wasextracted with DCM (2×20 mL). The organic layer was dried over Na₂SO₄,filtered and concentrated in vacuo to give the title compound (46.0 mg,98% yield) as yellow solid. LC-MS (ESI⁺) m/z 464.1 (M+H)⁺.

Methyl6-bromo-2-[4-(hydroxymethyl)-1-piperidyl]-1,3-benzothiazole-5-carboxylate(Intermediate BCJ)

Step 1—Methyl 2-sulfanyl-1,3-benzothiazole-5-carboxylate

To a solution of methyl 3-amino-4-bromo-benzoate (5.00 g, 21.7 mmol, CAS#46064-79-3) in pyridine (60 mL) was addedethoxycarbothioylsulfanylpotassium (5.23 g, 32.6 mmol) at 25° C. Thereaction mixture was stirred at 110° C. for 12 hours under N₂. Oncompletion, the reaction mixture was concentrated in vacuo to removepyridine, then the mixture was redissolved with 50 mL H₂O and aq 1N HClwas added to adjust pH=1-2. The above mixture was filtered and thefiltrate was concentrated in vacuo to give the title compound (4.00 g,65% yield, 80% purity) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ13.98 (s, 1H), 7.84 (s, 2H), 7.80 (s, 1H), 3.88 (s, 3H).

Step 2—Methyl 2-methylsulfanyl-1,3-benzothiazole-5-carboxylate

To a solution of methyl 2-sulfanyl-1,3-benzothiazole-5-carboxylate (3.80g, 16.8 mmol) and K₂CO₃ (245 mg, 1.78 mmol) in EA (50 mL) was added CH₃I(33.7 mmol, 2.10 mL). The mixture was stirred at 25° C. for 2 hours. Oncompletion, the mixture was filtered and washed with EA (3×50 mL). Theorganic phase was concentrated in vacuo and the residue was purified byflash silica gel chromatography (PE:EA=5:1) to give the title compound(3.00 g, 74% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.54(d, J=0.8 Hz, 1H), 7.98 (dd, J=1.6, 8.4 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H),3.97 (s, 3H), 2.82 (s, 3H); LC-MS (ESL) m/z 240.2 (M+H)⁺.

Step 3—Methyl 2-methylsulfonyl-1,3-benzothiazole-5-carboxylate

To a solution of methyl 2-methylsulfanyl-1,3-benzothiazole-5-carboxylate(2.00 g, 8.36 mmol) in DCM (20 mL) was added m-CPBA (1.87 g, 10.8 mmol).The mixture was stirred at 25° C. for 6 hours. On completion, to themixture was added sat. NaHCO₃. (20 mL) and sat. Na₂S₂O₃ (20 mL), thenthe mixture was extracted with DCM 90 mL (3×30 mL). The combined organiclayers were washed with brine (30 mL), dried over Na₂SO₄, filtered andthe filtrate was concentrated in vacuo to give the title compound (2.20g, 97% yield) as a white solid. LC-MS (ESI⁺) m/z 272.0 (M+H)⁺.

Step 4—Methyl2-[4-(hydroxymethyl)-1-piperidyl]-1,3-benzothiazole-5-carboxylate

To a solution of methyl 2-methylsulfonyl-1,3-benzothiazole-5-carboxylate(1.10 g, 4.05 mmol) and 4-piperidylmethanol (933 mg, 8.11 mmol, CAS#6457-49-4) in DMA (10 mL). The mixture was stirred at 130° C. for 0.5hr under microwave irradiation. On completion, the reaction mixture wasdiluted with 100 mL water and extracted with EA 150 mL (3×50 mL). Thecombined organic layers were washed with 100 mL brine, dried overNa₂SO₄, filtered and concentrated in vacuo to give the title compound(1.30 g, crude) as white solid. LC-MS (ESI⁺) m/z 307.1 (M+H)⁺.

Step 5—Methyl6-bromo-2-[4-[(2,2,2-trifluoroacetyl)oxymethyl]-1-piperidyl]-1,3-benzothiazole-5-carboxylate

To a solution of methyl2-[4-(hydroxymethyl)-1-piperidyl]-1,3-benzothiazole-5-carboxylate (1.20g, 3.92 mmol) in TLA (10 mL) and H₂SO₄ (5 mL) and DCM (10 mL) was addedNBS (906 mg, 5.09 mmol). The mixture was stirred at 0° C. for 2 hrs. Oncompletion, the reaction mixture was diluted with 50 mL ice water andextracted with DCM 150 mL (3×50 mL). The combined organic layers werewashed with 100 mL brine, dried over Na₂SO₄, filtered and concentratedin vacuo to give the title compound (2.00 g, crude) as yellow oil. LC-MS(ESI⁺) m/z 482.8 (M+3)⁺.

Step 6—Methyl6-bromo-2-[4-(hydroxymethyl)-1-piperidyl]-1,3-benzothiazole-5-carboxylate

To a solution of methyl6-bromo-2-[4-[(2,2,2-trifluoroacetyl)oxymethyl]-1-piperidyl]-1,3-benzothiazole-5-carboxylate(2.00 g, 4.16 mmol) in MeOH (60 mL) was added K₂CO₃ (1.72 g, 12.4 mmol).The mixture was stirred at 25° C. for 2 hours. On completion, thereaction mixture was filtered and concentrated in vacuo. The residuephase was purified by reverse phase (0.1% LA condition) to give thetitle compound (400 mg, 24% yield) as yellow solid. LC-MS (ESI⁺) m/z387.0 (M+3)⁺.

2-Methyloxazole-4-carboxamide (Intermediate BEX)

Step 1—2-Methyloxazole-4-carbonyl chloride

To a solution of 2-methyloxazole-4-carboxylic acid (2.00 g, 15.7 mmol,CAS #23062-17-1) and DML (11.5 mg, 157 umol) in DCM (20 mL) was added(COCl)₂ (4.99 g, 39.3 mmol, 3.44 mL) at 0° C. The mixture was stirred at20° C. for 4 hrs. On completion, the reaction mixture was concentratedin vacuo to give the title compound (2.00 g, 87% yield) as a yellowsolid. ¹H NMR (400 MHz, CDCl₃) δ 8.34 (s, 1H), 2.54 (s, 3H).

Step 2—2-Methyloxazole-4-carboxamide

To a solution of NH₃.H₂O (9.63 g, 68.7 mmol, 10.5 mL, 25% solution) wasadded a solution of 2-methyloxazole-4-carbonyl chloride (2.00 g, 13.7mmol) in THF (5 mL) at 0° C. The mixture was stirred at 20° C. for 0.5hr. On completion, the reaction mixture was concentrated in vacuo toremove THF. Then the mixture was filtered, the filter cake was washedwith water and dried in vacuo to give the title compound (1.30 g, 75%yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (s, 1H),7.63-7.34 (m, 2H), 2.44 (s, 3H), LC-MS (ESI⁺) m/z 128.1 (M+H)⁺.

N-[2-(4-formyl-1-piperidyl)-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]-2-methyl-oxazole-4-carboxamide(Intermediate BFP)

Step 1—Methyl2-[4-(hydroxymethyl)-1-piperidyl]-6-[(2-methyloxazole-4-carbonyl)amino]-1,3-benzothiazole-5-carboxylate

A mixture of methyl6-bromo-2-[4-(hydroxymethyl)-1-piperidyl]-1,3-benzothiazole-5-carboxylate(200 mg, 519 umol, Intermediate BCJ), 2-methyloxazole-4-carboxamide(72.0 mg, 571 umol, Intermediate BEX), Cs₂CO₃ (338.27 mg, 1.04 mmol),Xantphos (60.0 mg, 103 umol) and Pd₂(dba)₃ (47.5 mg, 51.9 umol) indioxane (1 mL) was stirred at 80° C. for 24 hrs under N₂. On completion,the reaction mixture was filtered and concentrated in vacuo. The residuewas purified by silica gel chromatography (PE:EA=1:3) to give the titlecompound (90.0 mg, 40% yield) as yellow solid. 1H NMR (400 MHz, CDCl₃) δ12.23 (s, 1H), 9.21 (s, 1H), 8.25 (s, 1H), 8.20 (s, 1H), 4.19 (d, J=12.0Hz, 2H), 4.00 (s, 3H), 3.57 (d, J=6.0 Hz, 2H), 3.17 (t, J=12.8 Hz, 2H),2.58 (s, 3H), 2.49 (s, 1H), 1.95-1.76 (m, 2H), 1.48-1.33 (m, 3H).

Step2—N-[5-(1-hydroxy-1-methyl-ethyl)-2-[4-(hydroxymethyl)-1-piperidyl]-1,3-benzothiazol-6-yl]-2-methyl-oxazole-4-carboxamide

To a solution of methyl2-[4-(hydroxymethyl)-1-piperidyl]-6-[(2-methyloxazole-4-carbonyl)amino]-1,3-benzothiazole-5-carboxylate(150 mg, 348 umol) in THF (2 mL) was added MeMgBr (3 M, 1.16 mL) at 0°C. The reaction mixture was stirred at 25° C. for 1 hr. On completion,the reaction mixture was quenched with saturated NH₄Cl aqueous (1 mL),diluted with water (10 mL), and extracted with EA (3×10 mL). Thecombined organic layers was washed with brine (2×10 mL), dried overNa₂SO₄, filtered and concentrated in vacuo to give the title compound(142 mg, 94% yield) as yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 11.07 (s,1H), 8.74 (s, 1H), 8.17 (s, 1H), 7.51 (s, 1H), 4.19-4.14 (m, 2H), 3.56(d, J=5.2 Hz, 2H), 3.18-3.11 (m, 2H), 2.52 (s, 3H), 1.90-1.88 (m, 1H),1.75 (s, 6H), 1.42-1.33 (m, 4H).

Step3—N-[2-(4-formyl-1-piperidyl)-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]-2-methyl-oxazole-4-carboxamide

To a solution ofN-[5-(1-hydroxy-1-methyl-ethyl)-2-[4-(hydroxymethyl)-1-piperidyl]-1,3-benzothiazol-6-yl]-2-methyl-oxazole-4-carboxamide (140 mg, 325 umol) in DCM (2 mL)was added DMP (179 mg, 422 umol). The reaction mixture was stirred at25° C. for 2 hrs. On completion, the reaction mixture was quenched withsaturated Na₂S₂O₃ aqueous (1 mL), then added saturated NaHCO₃ aqueousuntil the pH=7˜8. The reaction mixture was diluted with water (10 mL),and extracted with DCM (3×10 mL). The combined organic layer was washedwith brine (2×10 mL), dried over Na₂SO₄, filtered and concentrated invacuo to give the title compound (107 mg, 76% yield) as brown solid. 1HNMR (400 MHz, CDCl₃) δ 11.09 (s, 1H), 9.72 (s, 1H), 8.76 (s, 1H), 8.18(s, 1H), 7.52 (s, 1H), 4.08-4.03 (m, 2H), 3.36-3.29 (m, 2H), 2.53 (s,3H), 2.11-2.08 (m, 1H), 1.88-1.76 (m, 4H), 1.75 (s, 6H).

3-[3-Methyl-4-[4-(methylamino)-1-piperidyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate AOK)

Step 1—Tert-butylN-[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]-N-methyl-carbamate

To a solution of3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (500mg, 1.48 mmol, Intermediate HP), tert-butyl Nmethyl-N-(4-piperidyl)carbamate (633 mg, 2.96 mmol, CAS #108612-54-0)and 4 Å molecular sieves (500 mg) in toluene (10 mL) was added[2-(2-aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (229 mg, 295umol), RuPhos (138 mg, 295 umol) and LiHMDS (1.00 M, 8.87 mL) under N₂atmosphere. The mixture was stirred at 80° C. for 1 hr under N₂atmosphere. On completion, the mixture was concentrated in vacuo. Theresidue was diluted with DMF (6 mL), filtered and the filtrate wasacidified with FA until the pH=5. The filtrate was concentrated invacuo. The residue was purified by reverse phase (0.1% FA) and silicagel column (PE:EA=1:1) to give the title compound (70 mg, 10% yield) asa yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 7.01-6.84 (m,3H), 5.42-5.27 (m, 1H), 3.64 (s, 3H), 3.36-3.33 (m, 1H), 3.22-3.09 (m,2H), 2.94-2.77 (m, 3H), 2.75 (s, 3H), 2.70-2.57 (m, 2H), 2.04-1.98 (m,1H), 1.95-1.84 (m, 2H), 1.72-1.59 (m, 2H), 1.42 (s, 9H), LC-MS (ESI⁺)m/z 472.2 (M+H)⁺.

Step2—3-[3-Methyl-4-[4-(methylamino)-1-piperidyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]-N-methylcarbamate(70.0 mg, 148 umol) in DCM (3.00 mL) was added HCl/dioxane (4.00 M, 2.00mL). The mixture was stirred at 25° C. for 0.5 hr. On completion, themixture was concentrated in vacuo to give the title compound (60 mg, 99%yield, HCl salt) as a yellow solid. LC-MS (ESI⁺) m/z 372.3 (M+H)⁺.

3-[3-methyl-2-oxo-4-[2-(4-piperidyl)ethyl]benzimidazol-1-yl]piperidine-2,6-dione(Intermediate APY)

Step1—Tert-butyl4-[2-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]ethyl]piperidine-1-carboxylate

To an 40 mL vial equipped with a stir bar was added3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (868mg, 2.57 mmol, Intermediate HP), tert-butyl 4-(2-bromoethyl)piperidine-1-carboxylate (900 mg, 3.08 mmol, CAS #169457-73-2),Ir[dF(CF₃)ppy]₂(dtbpy)(PF₆) (28.8 mg, 25.7 umol), NiCl₂.glyme (2.82 mg,12.8 umol), dtbbpy (4.13 mg, 15.4 umol), TTMSS (638 mg, 2.57 mmol, 792uL) and Na₂CO₃ (544 mg, 5.13 mmol) in DME (20 mL). The reaction mixturewas stirred and irradiated with a 34 W blue LED lamp at 25° C. for 14hrs. On completion, the reaction mixture was filtered and the residuewas concentrated in vacuo to give a residue. The crude product waspurified by reverse phase flash (0.1% FA condition) to give the titlecompound (470 mg, 39% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆)511.03 (br s, 1H), 6.98-6.92 (m, 2H), 6.90-6.83 (m, 1H), 5.35 (dd,J=5.2, 12.4 Hz, 1H), 3.96-3.92 (m, 2H), 3.55 (s, 3H), 2.95-2.83 (m, 3H),2.75-2.57 (m, 4H), 2.03-1.95 (m, 1H), 1.74 (d, J=12.4 Hz, 2H), 1.53 (t,J=6.0 Hz, 3H), 1.39 (s, 9H), 1.13-0.99 (m, 2H); LC-MS (ESI⁺) m/z 415.2(M+H−56)⁺.

Step2—3-[3-Methyl-2-oxo-4-[2-(4-piperidyl)ethyl]benzimidazol-1-yl]piperidine-2,6-dione

To a solution oftert-butyl4-[2-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]ethyl]piperidine-1-carboxylate (200 mg, 425 umol) in DCM (3.0 mL) was addedHCl/dioxane (4 M, 1.0 mL). The reaction mixture was stirred at 25° C.for 1 hr. On completion, the reaction mixture was concentrated in vacuoto give the title compound (170 mg, 90% yield, HCl salt) as orangesolid. LC-MS (ESI⁺) m/z 371.2 (M+H)⁺.

Tert-butyl 4-prop-2-ynylpiperidine-1-carboxylate (Intermediate AKO)

To a solution of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (500mg, 2.20 mmol, CAS #142374-19-4), K₂CO₃ (912 mg, 6.60 mmol) in MeOH (15mL) was added 1-diazo-1-dimethoxyphosphoryl-propan-2-one (507 mg, 2.64mmol, CAS #90965-06-3) at 0° C. The mixture was stirred at 25° C. for 16hours. On completion, the mixture was concentrated in vacuo. The mixturewas diluted with H₂O (30 mL), then extracted with EA (3×20 mL). Theorganic layers were washed with brine (2×15 mL), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo to give the title compound(490 mg, 99% yield) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 4.25-4.03(m, 2H), 2.78-2.65 (m, 2H), 2.22-2.13 (m, 2H), 2.00 (t, J=2.8 Hz, 1H),1.85-1.72 (m, 2H), 1.72-1.60 (m, 1H), 1.48 (s, 9H), 1.30-1.15 (m, 2H).

3-[3-Methyl-2-oxo-4-[3-(4-piperidyl)propyl]benzimidazol-1-yl]piperidine-2,6-dione(Intermediate AKP)

Step 1—Tert-butyl4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynyl]piperidine-1-carboxylate

To a solution of tert-butyl 4-prop-2-ynylpiperidine-1-carboxylate (390mg, 1.75 mmol, Intermediate AKO),3-(4-bromo-3-methyl-2-oxobenzimidazol-1-yl)piperidine-2,6-dione (393 mg,1.16 mmol, Intermediate HP) in DMSO (4 mL) was added Pd(PPh₃)₂Cl₂ (163mg, 232 umol), CuI (44.3 mg, 232 umol) and DIPEA (752 mg, 5.82 mmol)under N₂. The mixture was stirred at 80° C. for 3 hours. On completion,the mixture was filtered and concentrated in vacuo. The mixture waspurified by reverse phase: (0.1% FA) to give the title compound (450 mg,80% yield) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.12 (s, 1H),7.17-6.95 (m, 3H), 5.45-5.33 (m, 1H), 4.06-3.89 (m, 2H), 3.63 (s, 3H),2.98-2.82 (m, 1H), 2.78-2.69 (m, 2H), 2.66-2.59 (m, 1H), 2.56-2.52 (m,1H), 2.49-2.45 (m, 2H), 2.11-1.97 (m, 1H), 1.82-1.71 (m, 3H), 1.39 (s,9H), 1.25-1.10 (m, 2H), LC-MS (ESI⁺) m/z 503.3 (M+Na)⁺.

Step 2—Tert-butyl4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propyl]piperidine-1-carboxylate

To a solution of tert-butyl4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynyl]piperidine-1-carboxylate(500 mg, 1.04 mmol) in THF (50 mL) was added Pd/C (250 mg) and Pd(OH)₂/C(250 mg). The mixture was stirred at 15° C. for 16 hours under H₂ (15psi). On completion, the mixture was filtered and the filtrate was driedin vacuo to give the title compound (500 mg, 99% yield) as white solid.¹H NMR (400 MHz, CDCl₃) δ 8.46 (s, 1H), 7.00 (s, 1H), 6.93-6.88 (m, 1H),6.72-6.65 (m, 1H), 5.27-5.19 (m, 1H), 4.77 (s, 2H), 4.18-3.98 (m, 2H),3.67 (s, 3H), 2.95-2.89 (m, 2H), 2.86-2.79 (m, 1H), 2.78-2.73 (m, 1H),2.72-2.62 (m, 2H), 2.25-2.16 (m, 1H), 1.78-1.74 (m, 2H), 1.69-1.66 (m,2H), 1.47 (s, 9H), 1.41-1.37 (m, 2H), 1.17-1.04 (m, 2H).

Step3—3-[3-Methyl-2-oxo-4-[3-(4-piperidyl)propyl]benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propyl]piperidine-1-carboxylate (100 mg, 206 umol) in DCM (3.0 mL) was addedHCl/dioxane (4.0 M, 2.0 mL). The mixture was stirred at 20° C. for 0.5hour. On completion, the mixture was concentrated in vacuo to give thetitle compound (85.0 mg, 97% yield) as white solid. LC-MS (ESI⁺) m/z385.3 (M+H)⁺.

3-[3-Methyl-2-oxo-4-[3-(4-piperidyl)prop-1-ynyl]benzimidazol-1-yl]piperidine-2,6-dione(Intermediate AZF)

To a solution of tert-butyl4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynyl]piperidine-1-carboxylate (80 mg, 166.47 umol, synthesized via Step1 of Intermediate AKP) in DCM (5.00 mL) was added TFA (770 mg, 6.75mmol, 0.50 mF). The mixture was stirred at 20° C. for 1 hr. Oncompletion, the reaction mixture was concentrated in vacuo to give thetitle compound (80.0 mg, 97% yield, TFA) as a yellow solid. FC-MS (ESL)m/z 381.1 (M+H)⁺.

2-[6-Amino-2-[4-(hydroxymethyl)cyclohexyl]-1,3-benzothiazol-5-yl]propan-2-ol(Intermediate BHD)

Step 1—Methyl2-[4-(benzyloxymethyl)cyclohexyl]-6-[(2,4-dimethoxyphenyl)methylamino]-1,3-benzothiazole-5-carboxylate

To a solution of methyl2-[4-(benzyloxymethyl)cyclohexyl]-6-bromo-1,3-benzothiazole-5-carboxylate(3.00 g, 6.32 mmol, synthesized via Steps 1-3 of Intermediate BAW) indioxane (20 mL) was added Pd₂(dba)₃ (579 mg, 632 umol), Xantphos (731mg, 1.26 mmol), Cs₂CO₃ (4.12 g, 12.6 mmol) and (2,4-dimethoxyphenyl)methanamine (1.27 g, 7.59 mmol). The mixture was stirred at 80° C. for 3hours. On completion, the mixture was concentrated in vacuo to give aresidue. The residue was purified by column chromatography (SiO₂,PE:EA=5:1 to 0:1) to give the title compound (3.2 g, 92% yield) as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ 8.44 (s, 1H), 7.97 (t, J=5.6 Hz,1H), 7.30-7.20 (m, 4H), 7.10 (d, J=8.4 Hz, 1H), 6.92 (s, 1H), 6.42 (d,J=2.4 Hz, 1H), 6.35 (dd, J=2.4, 8.4 Hz, 1H), 4.44 (s, 2H), 4.31 (d,J=5.6 Hz, 2H), 3.81 (s, 3H), 3.78 (s, 3H), 3.71 (s, 3H), 3.26 (d, J=6.4Hz, 2H), 2.87 (tt, J=3.6, 12.0 Hz, 1H), 2.19-2.10 (m, 2H), 1.95-1.88 (m,2H), 1.72-1.61 (m, 1H), 1.60-1.47 (m, 3H), 1.15-1.02 (m, 2H).

Step 2—Methyl6-amino-2-[4-(benzyloxymethyl)cyclohexyl]-1,3-benzothiazole-5-carboxylate

To a mixture of methyl2-[4-(benzyloxymethyl)cyclohexyl]-6-[(2,4-dimethoxyphenyl)methylamino]-1,3-benzothiazole-5-carboxylate(3.60 g, 6.42 mol) in THF (30 mL) was added HCl/MeOH (4 M, 3.21 mL) andthe mixture was stirred at 20° C. for 0.5 hour. On completion, themixture was concentrated in vacuo to give the title compound (1.90 g,72% yield) as a brown solid. ¹H NMR (400 MHz, CDCl₃) δ 8.50 (s, 1H),7.41-7.29 (m, 5H), 7.07 (s, 1H), 5.75 (s, 2H), 4.54 (s, 2H), 3.93 (s,3H), 3.36 (d, J=6.4 Hz, 2H), 2.98 (tt, J=3.6, 12.0 Hz, 1H), 2.31-2.20(m, 2H), 2.08-1.98 (m, 2H), 1.84-1.74 (m, 1H), 1.73-1.55 (m, 3H),1.24-1.14 (m, 2H).

Step 3—Methyl6-amino-2-[4-(hydroxymethyl)cyclohexyl]-1,3-benzothiazole-5-carboxylate

To a mixture of methyl6-amino-2-[4-(benzyloxymethyl)cyclohexyl]-1,3-benzothiazole-5-carboxylate(1.70 g, 4.17 mmol) in THF (15 mL) and MeOH (15 mL) was added Pd/C (100mg, 10 wt %), Pd(OH)2/C (100 mg, 10 wt %) and HCl (12 M, 345 uL) underH₂ (15 psi). The mixture was stirred at 25° C. for 12 hours. Oncompletion, the mixture was filtered and concentrated in vacuo to givethe residue. The residue was purified by column chromatography (SiO₂,PE:EA=5:1 to 0:1) to give the title compound (850 mg, 64% yield) as abrown solid. ¹H NMR (400 MHz, DMSO-ds) δ 8.20 (s, 1H), 7.27 (s, 1H),6.67 (s, 2H), 4.44 (t, J=5.2 Hz, 1H), 3.84 (s, 3H), 3.26 (t, J=5.6 Hz,2H), 2.98-2.89 (m, 1H), 2.17-2.08 (m, 2H), 1.86 (dd, J=2.4, 13.2 Hz,2H), 1.56-1.46 (m, 2H), 1.44-1.36 (m, 1H), 1.12-1.02 (m, 2H).

Step4—2-[6-Amino-2-[4-(hydroxymethyl)cyclohexyl]-1,3-benzothiazol-5-yl]propan-2-ol

To a mixture of methyl6-amino-2-[4-(hydroxymethyl)cyclohexyl]-1,3-benzothiazole-5-carboxylate(600 mg, 1.87 mmol) in THF (5 mL) was added MeMgBr (3 M, 3.12 mL) at 0°C. The mixture was stirred at 25° C. for 3 hours. On completion, themixture was quenched by water (60 mL) and the aqueous phase wasextracted with ethyl acetate (3×30 mL). The combined organic phase waswashed with brine (2×50 mL), dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give the residue. The residue was purified bycolumn chromatography (SiO₂, petroleum ether/ethyl acetate=3:1 to 0:1)to give the title compound (490 mg, 73% yield) as a brown solid. ¹H NMR(400 MHz, DMSO-d₆) δ 7.55 (s, 1H), 7.08 (s, 1H), 5.66 (s, 2H), 5.36 (s,1H), 4.44 (t, J=5.2 Hz, 1H), 3.26 (t, J=5.6 Hz, 2H), 2.94-2.86 (m 1H),2.15-2.08 (m, 2H), 1.87-1.83 (m, 2H), 1.57 (s, 6H), 1.54-1.47 (m, 2H),1.43-1.39 (m, 1H), 1.12-1.01 (m, 2H).

N-[2-(4-formylcyclohexyl)-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]-5-(trifluoromethyl)pyrazine-2-carboxamide(Intermediate BHG)

Step1—N-[2-[4-(hydroxymethyl)cyclohexyl]-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]-5-(trifluoromethyl)pyrazine-2-carboxamide

To a solution of 5-(trifluoromethyl)pyrazine-2-carboxylic acid (35.9 mg,187 umol, CAS #1060814-50-7) in DMF (2.0 mL) was added DIPEA (72.6 mg,561 umol, 97.8 uL) and CMPI (57.4 mg, 224 umol), the reaction mixturewas stirred at 15° C. for 30 mins. Then2-[6-amino-2-[4-(hydroxymethyl)cyclohexyl]-1,3-benzothiazol-5-yl]propan-2-ol(60 mg, 187 umol, Intermediate BHD) was added to the mixture, and thereaction mixture was stirred at 15° C. for 1 hour. On completion, thereaction mixture was concentrated in vacuo to give a residue. Theresidue was purified by reverse phase (0.1% FA condition) to give thetitle compound (50 mg, 54.0% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 12.64 (s, 1H), 9.52 (s, 1H), 9.32 (s, 1H), 9.07 (s, 1H), 7.90(s, 1H), 6.35 (s, 1H), 4.45 (t, J=5.2 Hz, 1H), 3.27 (t, J=5.6 Hz, 2H),3.11-2.95 (m, 1H), 2.22-2.14 (m, 2H), 1.92-1.83 (m, 2H), 1.64 (s, 6H),1.61-1.51 (m, 2H), 1.51-1.38 (m, 1H), 1.18-1.03 (m, 2H); LC-MS (ESI⁺)m/z 495.3 (M+1)⁺.

Step2—N-[2-(4-formylcyclohexyl)-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]-5-(trifluoromethyl)pyrazine-2-carboxamide

To a solution ofN-[2-[4-(hydroxymethyl)cyclohexyl]-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]-5-(trifluoromethyl)pyrazine-2-carboxamide (50 mg, 101 umol) inDCM (2.0 mL) was added DMP (51.4 mg, 121 umol), then the reactionmixture was stirred at 15° C. for 1 hour. On completion, the reactionmixture was quenched with Na₂S₂O₃ (10 mL) and extracted with DCM (2×20mL). The combined organic phase was washed with NaHCO₃ (15 mL) and brine(2×15 mL), dried over anhydrous Na₂SO₄, filtered and concentrated invacuo to give the title compound (45 mg, 90% yield) as a light yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.64 (s, 1H), 9.63 (s, 1H), 9.52 (s,1H), 9.32 (s, 1H), 9.08 (s, 1H), 7.91 (s, 1H), 6.35 (s, 1H), 3.15-3.04(m, 1H), 2.45-2.35 (m, 1H), 2.28-2.19 (m, 2H), 2.12-2.02 (m, 2H),1.74-1.65 (m, 2H), 1.64 (s, 6H), 1.47-1.35 (m, 2H).

N-[2-(4-formyl-1-piperidyl)-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide(Intermediate BHH)

Step 12-[4-(Hydroxymethyl)-1-piperidyl]-6-[[6-(trifluoromethyl)pyridine-2-carbonyl]amino]-1,3-benzothiazole-5-carboxylicacid

A mixture of 6-(trifluoromethyl)pyridine-2-carboxamide (315 mg, 1.66mmol, Intermediate ATI), methyl6-bromo-2-[4-(hydroxymethyl)-1-piperidyl]-1,3-benzothiazole-5-carboxylate(630 mg, 1.64 mmol, Intermediate BCJ), Cs₂CO₃ (1.07 g, 3.27 mmol),Pd₂(dba)₃ (149 mg, 163 umol) and Xantphos (94.6 mg, 163 umol) in dioxane(10.0 mL) was degassed and purged with N₂ three times. Then the mixturewas stirred at 80° C. for 16 hrs under N₂ atmosphere. On completion, thereaction mixture was filtered and the filtrate was concentrated in vacuoto give a residue. The residue was purified by reversed phase (0.1% FAcondition) to give the title compound (140 mg, 17% yield) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.59-13.05 (m, 1H), 9.25 (s, 1H),8.48-8.42 (m, 1H), 8.42-8.33 (m, 1H), 8.18 (d, J=7.6 Hz, 1H), 8.03 (s,1H), 7.71-6.99 (m, 1H), 4.65-4.46 (m, 1H), 4.05 (d, J=12.0 Hz, 2H),3.30-3.28 (m, 2H), 3.21-3.12 (m, 2H), 1.79 (d, J=12.0 Hz, 2H), 1.68 (d,J=3.2 Hz, 1H), 1.28-1.17 (m, 2H).

Step 2—Methyl2-[4-(hydroxymethyl)-1-piperidyl]-6-[[6-(trifluoromethyl)pyridine-2-carbonyl]amino]-1,3-benzothiazole-5-carboxylate

To a solution of2-[4-(hydroxymethyl)-1-piperidyl]-6-[[6-(trifluoromethyl)pyridine-2-carbonyl]amino]-1,3-benzothiazole-5-carboxylicacid (90.0 mg, 187 umol) in DMF (5.00 mL) was added K₂CO₃ (51.8 mg, 375umol) and Mel (106 mg, 749 umol, 46.6 uL) at 0° C. The mixture wasstirred at 20° C. for 2 hrs. On completion, the reaction mixture wasquenched by addition water (10 mL), and then extracted with EA (3×10mL). The combined organic layers were washed with brine (2×20 mL), driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo to give thetitle compound (90.0 mg, 97% yield) as a yellow solid. ¹H NMR (400 MHz,CDCl₃) δ 13.04-12.94 (m, 1H), 9.27 (s, 1H), 8.49 (d, J=7.6 Hz, 1H), 8.27(s, 1H), 8.12 (t, J=8.0 Hz, 1H), 7.88 (d, J=7.8 Hz, 1H), 4.20 (d, J=12.4Hz, 2H), 4.03 (s, 3H), 3.57 (d, J=6.0 Hz, 2H), 3.18 (t, J=12.0 Hz, 2H),1.91 (d, J=12.8 Hz, 2H), 1.87-1.79 (m, 1H), 1.45-1.37 (m, 2H).

Step3—N-[5-(1-hydroxy-1-methyl-ethyl)-2-[4-(hydroxymethyl)-1-piperidyl]-1,3-benzothiazol-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

To a solution of methyl2-[4-(hydroxymethyl)-1-piperidyl]-6-[[6-(trifluoromethyl)pyridine-2-carbonyl]amino]-1,3-benzothiazole-5-carboxylate (100 mg, 202 umol) in THF (4.00mL) was added MeMgBr (3 M, 337 uL) at 0° C. and the mixture was stirredat 0° C. for 4 hrs. On completion, the reaction mixture was quenched byaddition water (10 mL) at 0° C., and then extracted with EA (3×10 mL).The combined organic layers were washed with brine (2×20 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound (95.0 mg, 94% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 12.36 (s, 1H), 8.77 (s, 1H), 8.45 (s, 1H), 8.40-8.36 (m, 1H),8.16 (d, J=7.8 Hz, 1H), 7.41 (s, 1H), 5.94 (s, 1H), 4.54 (d, J=5.2 Hz,1H), 4.03 (d, J=8.0 Hz, 2H), 3.30 (s, 2H), 3.16-3.11 (m, 2H), 1.77 (d,J=11.6 Hz, 4H), 1.68-1.65 (m, 1H), 1.58 (s, 6H).

Step4—N-[2-(4-formyl-1-piperidyl)-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

To a solution ofN-[5-(1-hydroxy-1-methyl-ethyl)-2-[4-(hydroxymethyl)-1-piperidyl]-1,3-benzothiazol-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide(120 mg, 242 umol) in DCM (6.00 mL) was added DMP (123 mg, 291 umol,90.2 uL) and NaHCO₃ (61.2 mg, 728 umol) at 0° C. The mixture was stirredat 20° C. for 2 hrs. On completion, the reaction mixture was quenched byaddition saturated solution of Na₂S₂O₃ (5 mL), and saturated solution ofNaHCO₃ (4 mL), then extracted with DCM (3×10 mL). The combined organiclayer was washed with brine (2×20 mL), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo to give a residue. The residue waspurified by column chromatography (SiO₂) to give the title compound(40.0 mg, 33% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ12.37 (d, J=2.4 Hz, 1H), 9.63 (s, 1H), 8.79 (s, 1H), 8.46-8.42 (m, 1H),8.39-8.34 (m, 1H), 8.16 (d, J=7.2 Hz, 1H), 7.43 (s, 1H), 5.95 (s, 1H),3.97-3.92 (m, 2H), 3.31-3.27 (m, 2H), 2.70-2.64 (m, 1H), 2.01-1.96 (m,2H), 1.62-1.53 (m, 8H).

N-[2-(4-formylcyclohexyl)-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]pyridine-2-carboxamide(Intermediate BJF)

Step 1—Methyl2-[4-(benzyloxymethyl)cyclohexyl]-6-(pyridine-2-carbonylamino)-1,3-benzothiazole-5-carboxylate

To a solution of methyl2-[4-(benzyloxymethyl)cyclohexyl]-6-bromo-1,3-benzothiazole-5-carboxylate(1.00 g, 2.11 mmol, synthesized via Steps 1-3 of Intermediate BAW) andpyridine-2-carboxamide (283 mg, 2.32 mmol, CAS #1452-77-3) in dioxane(10 mL) was added Cs₂CO₃ (1.37 g, 4.22 mmol), Xantphos (243 mg, 421umol) and Pd₂(dba)₃ (193 mg, 210 umol) at 25° C. The reaction mixturewas stirred at 80° C. for 48 hours under N₂. On completion, the mixturewas filtered and the filtrate was concentrated in vacuo. The residue waspurified by column chromatography (SiO₂, petroleum ether/ethylacetate=20:1 to 3:1) to give the title compound (750 mg, 55% yield) asyellow solid. LC-MS (ESI⁺) m/z 516.1 (M+H)⁺.

Step 2—Methyl2-[4-(hydroxymethyl)cyclohexyl]-6-(pyridine-2-carbonylamino)-1,3-benzothiazole-5-carboxylate

To a solution of methyl2-[4-(benzyloxymethyl)cyclohexyl]-6-(pyridine-2-carbonylamino)-1,3-benzothiazole-5-carboxylate(400 mg, 775 umol) in DCM (15 mL) was added BCl₃ (1 M, 1.55 mL) at 25°C. The reaction mixture was stirred at 25° C. for 4 hours. Oncompletion, the reaction mixture was added of sat. aq. NaHCO₃ (3 mL),then the mixture was diluted with H₂O (50 mL) and extracted with EA(3×20 mL). The combined organic layers were washed with brine (2×15 mL),dried over Na₂SO₄, filtered and the filtrate was concentrated in vacuo.The residue was purified by column chromatography (SiO₂, petroleumether/ethyl acetate=10:1 to 1:1) to give the title compound (230 mg, 69%yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 13.19 (s, 1H), 9.59(s, 1H), 8.81 (d, J=4.0 Hz, 1H), 8.73 (s, 1H), 8.32 (d, J=8.0 Hz, 1H),7.98-7.88 (m, 1H), 7.55-7.46 (m, 1H), 7.27 (s, 1H), 4.06 (s, 3H), 3.55(d, J=6.0 Hz, 2H), 3.13-3.01 (m, 1H), 2.39-2.28 (m, 2H), 2.08-1.95 (m,2H), 1.77-1.67 (m, 2H), 1.65-1.60 (m, 1H), 1.27-1.14 (m, 2H).

Step 3N-[2-[4-(hydroxymethyl)cyclohexyl]-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]pyridine-2-carboxamide

To a solution of methyl2-[4-(hydroxymethyl)cyclohexyl]-6-(pyridine-2-carbonylamino)-1,3-benzothiazole-5-carboxylate(230 mg, 540 umol) in THF (6 mL) was added MeMgBr (3 M, 1.08 mL) at 0°C. The mixture was stirred at 0-25° C. for 2 hours. On completion, thereaction mixture was quenched with sat.aq NH₄Cl (3 mL) at 0° C., dilutedwith H₂O (30 mL) and extracted with EA (3×10 mL). The combined organiclayers were washed by brine (20 mL), dried over Na₂SO₄, filtered and thefiltrate was concentrated in vacuo. The residue was purified by reversephase (0.1% FA condition) to give the title compound (125 mg, 54% yield)as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.52 (s, 1H), 9.05 (s,1H), 8.75-8.70 (m, 1H), 8.21 (d, J=8.0 Hz, 1H), 8.12-8.05 (m, 1H), 7.87(s, 1H), 7.70-7.64 (m, 1H), 6.15 (s, 1H), 4.45 (t, J=5.2 Hz, 1H),3.30-3.25 (m, 2H), 3.08-2.98 (m, 1H), 2.21-2.14 (m, 2H), 1.92-1.83 (m,2H), 1.63 (s, 6H), 1.60-1.51 (m, 2H), 1.48-1.40 (m, 1H), 1.16-1.05 (m,2H); LC-MS (ESL) m/z 426.2 (M+H)⁺.

Step4—N-[2-(4-formylcyclohexyl)-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]pyridine-2-carboxamide

To a solution ofN-[2-[4-(hydroxymethyl)cyclohexyl]-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]pyridine-2-carboxamide (125 mg, 293 umol) in DCM (1.5 mL) wasadded DMP (161 mg, 381 umol) at 25° C. The reaction mixture was stirredat 25° C. for 1 hour. On completion, the reaction mixture was quenchedwith sat. aq. Na₂S₂O₃ (1 mL) and sat. aq. NaHCO₃ (1 mL), then dilutedwith H₂O (15 mL) and extracted with DCM (3×5 mL). The combined organiclayers were washed with brine (2×5 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (120 mg, 96% yield) asyellow solid. LC-MS (ESL) m/z 406.2 (M−17)⁺.

3-[4-(3,9-diazaspiro[5.5]undecan-3-yl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate BJG)

Step 1- Tert-butyl9-[3-methyl-2-oxo-1-(2-trimethylsilylethoxymethyl)benzimidazol-4-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate

To a solution of4-bromo-3-methyl-1-(2-trimethylsilylethoxymethyl)benzimidazol-2-one (5.0g, 13.9 mmol, Intermediate BED) and tert-butyl3,9-diazaspiro[5.5]undecane-3-carboxylate (3.74 g, 14.6 mmol, CAS#173405-78-2) in toluene (50 mL) was added RuPhos (1.31 g, 2.80 mmol),Pd₂(dba)₃ (1.28 g, 1.40 mmol), and t-BuONa (3.36 g, 34.9 mmol). Thereaction mixture was then stirred at 80° C. for 2 hours. On completion,the reaction mixture was filtered, and the filtrate was concentrated invacuo to give a residue. The residue was purified by reverse phase (0.1%FA condition) to give the title compound (4.4 g, 59% yield) as yellowoil. LC-MS (ESI⁺) m/z 531.5 (M+1)⁺.

Step 2—Tert-butyl9-(3-methyl-2-oxo-1H-benzimidazol-4-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

To a solution of tert-butyl9-[3-methyl-2-oxo-1-(2-trimethylsilylethoxymethyl)benzimidazol-4-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate(4.4 g, 8.29 mmol) in THF (40 mL) was added TBAF (10.8 g, 41.4 mmol),and the reaction mixture was stirred at 75° C. for 24 hours. Oncompletion, the reaction mixture was diluted with H₂O (20 mL), and thenextracted with EA (2×100 mL). The combined organic layer was washed withbrine (2×200 mL), dried over Na₂SO₄, filtered and concentrated in vacuoto give a residue. The residue was purified by column chromatography(SiO₂, petroleum ether/ethyl acetate=10/1 to 2/1, PE/EA=1/1) to give thetitle compound (2.3 g, 69% yield) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 10.21 (s, 1H), 7.00-6.96 (m, 1H), 6.94-6.85 (m, 2H), 3.76 (s,3H), 3.47-3.40 (m, 4H), 3.04-2.86 (m, 4H), 1.79-1.58 (m, 6H), 1.48 (s,9H), 1.46-1.35 (m, 2H); LC-MS (ESI⁺) m/z 401.2 (M+1)⁺.

Step 3—Tert-butyl9-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-4-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate

To a solution of tert-butyl9-(3-methyl-2-oxo-1H-benzimidazol-4-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate(2.2 g, 5.49 mmol) in THF (20 mL) was added t-BuOK (924 mg, 8.24 mmol)at 0° C., and the mixture was stirred at 0° C. for 0.5 hour. Then asolution of [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]trifluoromethanesulfonate (2.30 g, 6.04 mmol, Intermediate IQ) in THF(20 mL) was added dropwise to the mixture, and the reaction mixture wasstirred at 20° C. for 16 hours. On completion, the mixture was acidifiedwith HCOOH to pH=3-5, diluted with water (100 mL), then extracted withEA (2×100 mL). The organic layer was washed with brine (100 mL), andthen concentrated in vacuo to give a residue. The residue was purifiedby reverse phase (0.1% FA condition) to give the title compound (2.3 mg,66% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.40-7.34 (m,2H), 6.94-6.85 (m, 2H), 6.84-6.81 (m, 2H), 6.28 (d, J=7.6 Hz, 1H), 5.21(dd, J=5.2, 12.8 Hz, 1H), 5.03-4.92 (m, 2H), 3.80 (s, 3H), 3.76 (s, 3H),3.50-3.38 (m, 4H), 3.04-2.97 (m, 1H), 2.97-2.88 (m, 4H), 2.87-2.77 (m,1H), 2.68-2.55 (m, 1H), 2.19-2.12 (m, 1H), 1.81-1.72 (m, 2H), 1.70-1.61(m, 4H), 1.48 (s, 9H), 1.46-1.37 (m, 2H); LC-MS (ESI⁺) m/z 632.5 (M+1)⁺.

Step4—3-[4-(3,9-diazaspiro[5.5]undecan-3-yl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl9-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-4-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (500 mg,791 umol) in TFA (2.4 mL) was added TfOH (850 mg, 5.66 mmol, 500 uL),and the reaction mixture was stirred at 65° C. for 12 hours. Oncompletion, the reaction mixture concentrated in vacuo to give aresidue. The residue was purified by reverse phase (0.1% FA condition)to give the title compound (250 mg, 69% yield, FA salt) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.95 (s, 1H), 9.39 (s, 1H),7.01-6.94 (m, 2H), 6.91-6.83 (m, 1H), 5.35 (dd, J=5.2, 12.8 Hz, 1H),3.62 (s, 3H), 3.07-2.97 (m, 4H), 2.95-2.81 (m, 5H), 2.72-2.57 (m, 2H),2.05-1.93 (m, 1H), 1.85-1.66 (m, 4H), 1.63-1.45 (m, 4H).

3-[3-methyl-4-[3-(methylamino)prop-1-ynyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate BJH)

Step 1—Tert-butyl N-methyl-N-prop-2-ynyl-carbamate

To a solution of tert-butyl N-prop-2-ynylcarbamate (5.0 g, 32.2 mmol,CAS #92136-39-5) DMF (50 mL) was added NaH (1.42 g, 35.4 mmol, 60%dispersion in mineral oil) at 0° C., and the mixture was stirred at 0°C. for 0.5 hr. Next, Mel (5.94 g, 41.8 mmol, 2.61 mL) was added to themixture, and the reaction mixture was stirred at 50° C. for 16 hours. Oncompletion, the mixture was diluted with water (120 mL) and extractedwith EA (3×50 mL). The combined organic layer was dried over Na₂SO₄,filtered and concentrated in vacuo to give the title compound (5.4 g,99% yield) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 4.03 (s, 2H), 2.91(s, 3H), 2.21 (t, J=2.4 Hz, 1H), 1.46 (s, 9H).

Step 2—Tert-butylN-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynyl]-N-methyl-carbamate

To a solution of tert-butyl N-methyl-N-prop-2-ynyl-carbamate (2.25 g,13.3 mmol) and3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (3.0 g,8.87 mmol, Intermediate HP) in DMF (30 mL) was added CuI (168 mg, 887umol), Cs₂CO₃ (11.5 g, 35.4 mmol), Pd(PPh₃)₂Cl₂ (622 mg, 887 umol), 4AMS (500 mg), and the reaction mixture was stirred at 80° C. for 2 hours.On completion, the mixture was filtered, and the filtrate wasconcentrated in vacuo to give a residue. The residue was purified byreverse phase (0.1% FA condition) to give the title compound (2.0 g, 53%yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.33 (s, 1H), 7.15(dd, J=0.8, 8.0 Hz, 1H), 6.98 (t, J=8.0 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H),5.21 (dd, J=5.2, 12.4 Hz, 1H), 4.29 (s, 2H), 3.76 (s, 3H), 2.98 (s, 3H),2.94-2.69 (m, 3H), 2.27-2.17 (m, 1H), 1.49 (s, 9H); LC-MS (ESI⁺) m/z449.3 (M+Na)⁺.

Step3—3-[3-Methyl-4-[3-(methylamino)prop-1-ynyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynyl]-N-methyl-carbamate (70 mg, 164 umol) in DCM (2.0 mL) was added TFA(770 mg, 6.75 mmol, 0.5 mL), the reaction mixture was stirred at 20° C.for 30 min. On completion, the residue was filtered and the filtrate wasconcentrated in vacuo to give the title compound (70 mg, 96% yield, TFAsalt) as yellow oil. LC-MS (ESI⁺) m/z 449.3 (2M+H)⁺.

Benzyl N-[2-(aminomethyl)spiro[3.5]nonan-7-yl]-N-methyl-carbamate(Intermediate ANJ))

Step 1—Tert-butyl N-methyl-N-(4-methylenecyclohexyl)carbamate

A solution of n-BuLi (2.5 M, 66.0 mL) was added to a mixture ofmethyltriphenylphosphonium bromide (58.9 g, 165 mmol) in tetrahydrofuran(200 mL) at −10° C. After stirring for 30 min at −10° C., the yellowsuspension was cooled to −78° C. and a solution of tert-butylN-methyl-N-(4-oxocyclohexyl)carbamate (25.0 g, 110 mmol, CAS#400899-84-5) in tetrahydrofuran (100 mL) was added. After stirring for10 min at −78° C., the reaction mixture was warmed to 25° C. slowly andstirred for 3 hrs. On completion, the reaction mixture was quenched withsaturated ammonium chloride (20 mL), then extracted with ethyl acetate(3×100 mL). The combined organic layers were washed with brine (100 mL),dried over anhydrous sodium sulfate, filtered and the filtrate wasconcentrated in vacuo. The residue was purified by column chromatography(Petroleum ether/Ethyl acetate=40/1) to give the title compound (23.7 g,96% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 4.66 (s, 2H),4.33-3.94 (m, 1H), 2.72 (s, 3H), 2.47-2.32 (m, 2H), 2.24-2.10 (m, 2H),1.84-1.75 (m, 2H), 1.54-1.49 (m, 2H), 1.48 (m, 9H).

Step 2—N-methyl-4-methylene-cyclohexanamine

To a solution of tert-butyl N-methyl-N-(4-methylenecyclohexyl)carbamate(5.00 g, 22.2 mmol) in DCM (10 mL) was added tertfluoroacetic acid (7.70g, 67.5 mmol, 5.00 mL). The reaction mixture was stirred at 20° C. for 2hrs. On completion, the reaction mixture was concentrated in vacuo togive the title compound (5.31 g, 100% yield, TFA salt) as colorless oil.The product was unstable which was used for the next step withoutpurification. ¹H NMR (400 MHz, CDCl₃) δ 4.77 (s, 2H), 3.27-3.06 (m, 1H),2.76-2.73 (m, 3H), 2.50-2.42 (m, 2H), 2.22-2.05 (m, 4H), 1.58-1.50 (m,2H).

Step 3—Benzyl N-methyl-N-(4-methylenecyclohexyl)carbamate

To a solution of N-methyl-4-methylene-cyclohexanamine (5.31 g, 22.2mmol, TFA salt) and NaHCO₃ (6.53 g, 77.7 mmol, 3.02 mL) in a mixedsolvent of ACN (50 mL) and H₂O (50 mL) was added CbzCl (5.68 g, 33.3mmol, 4.73 mL). The reaction mixture was stirred at 25° C. for 12 hrs.On completion, the reaction mixture was concentrated in vacuo to removeACN, and extracted with ethyl acetate (2×100 mL). The combined organiclayer was washed with brine (20 mL), dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The residue was purified bysilica gel chromatography (petroleum ether:ethyl acetate=50:1) to givethe title compound (4.00 g, 68% yield) as a colorless oil. ¹H NMR (400MHz, CDCl₃) δ 7.42-7.28 (m, 5H), 5.15 (s, 2H), 4.66 (t, J=1.6 Hz, 2H),4.33-4.01 (m, 1H), 2.79 (s, 3H), 2.37-2.34 (m, 2H), 2.18-2.15 (m, 2H),1.87-1.73 (m, 2H), 1.57-1.48 (m, 2H). LC-MS (ESI⁺) m/z 260.2 (M+H)⁺.

Step 4—BenzylN-(3,3-dichloro-2-oxo-spiro[3.5]nonan-7-yl)-N-methyl-carbamate

To a solution of benzyl N-methyl-N-(4-methylenecyclohexyl)carbamate(3.50 g, 13.5 mmol) in diethyl ether (70 mL) was added Zn/Cu complex (7g). Then a mixture of 2,2,2-trichloroacetyl chloride (7.36 g, 40.5 mmol,4.52 mL) in diethyl ether (140 mL) was added dropwise. The reactionmixture was stirred at 30° C. for 16 hrs. On completion, the reactionmixture was poured into saturated NaHCO₃ aqueous solution (100 mL) andfiltered through a pad of Celite and the filtrate was collected. Theorganic layer was dried over anhydrous Na₂SO₄ and concentrated in vacuoto get a residue. The residue was purified by silica gel chromatography(petroleum ether/ethyl acetate=5/l) to give the title compound (3.80 g,76% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.35-7.21 (m,5H), 5.08 (s, 2H), 4.19-4.02 (m, 1H), 2.93 (s, 2H), 2.76 (s, 3H),2.37-2.26 (m, 2H), 1.86-1.62 (m, 6H). LC-MS (ESI⁺) m/z 370.0 (M+H)⁺.

Step 5—Benzyl N-methyl-N-(2-oxospiro[3.5]nonan-7-yl)carbamate

To a solution of benzylN-(3,3-dichloro-2-oxo-spiro[3.5]nonan-7-yl)-N-methyl-carbamate (3.30 g,8.91 mmol) in acetic acid (10 mL) was added Zn (2.33 g, 35.6 mmol) at15° C. The reaction mixture was stirred at 80° C. for 3 hrs. Oncompletion, the reaction mixture was filtered and the filtrate wasdiluted with water (50 mL), then extracted with ethyl acetate (3×50 mL).The combined organic layers were washed saturated NaHCO₃ (30 mL) andbrine (30 mL), dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give the title compound (2.40 g, 89% yield) asa gum oil. ¹H NMR (400 MHz, CDCl₃) δ 7.46-7.28 (m, 5H), 5.15 (s, 2H),4.20-3.84 (m, 1H), 2.90-2.68 (m, 7H), 1.86-1.68 (m, 6H), 1.55-1.42 (m,2H); LC-MS (ESI⁺) m/z 302.2 (M+H)⁺.

Step 6—Benzyl N-(2-hydroxyspiro[3.5]nonan-7-yl)-N-methyl-carbamate

To a solution of benzyl N-methyl-N-(2-oxospiro[3.5]nonan-7-yl)carbamate(1.00 g, 3.32 mmol) in MeOH (10 mL) was added NaBH₄ (151 mg, 3.98 mmol)at 0° C., and the mixture was stirred at 25° C. for 1 h. On completion,the reaction mixture was quenched with water (5 mL). The mixture wasconcentrated in vacuo to remove methanol, then the solution wasextracted with ethyl acetate (3×20 mL). The combined organic layers werewashed with brine (10 mL), dried over anhydrous sodium sulfate, filteredand the filtrate was concentrated in vacuo to give the title compound(1.00 g, 99% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.44-7.28(m, 5H), 5.14 (s, 2H), 4.28 (q, J=7.2 Hz, 1H), 4.05-3.75 (m, 1H), 2.79(s, 3H), 2.40-2.27 (m, 1H), 2.22-2.11 (m, 1H), 1.71-1.64 (m, 3H),1.62-1.51 (m, 4H), 1.48-1.46 (m, 3H); LC-MS (ESI⁺) m/z 304.1 (M+H)⁺.

Step7—[7-[Benzyloxycarbonyl(methyl)amino]spiro[3.5]nonan-2-yl]methanesulfonate

To a solution of benzylN-(2-hydroxyspiro[3.5]nonan-7-yl)-N-methyl-carbamate (1.00 g, 3.30 mmol)in DCM (20 mL) was added TEA (1.00 g, 9.89 mmol, 1.38 mL) and MsCl (566mg, 4.94 mmol, 383 uL) at 0° C. The reaction mixture was stirred at 20°C. for 3 hrs. On completion, the reaction mixture was quenched withwater (10 mL). The organic layer was separated and washed with brine (50mL), dried over anhydrous sodium sulfate, filtered and concentrated invacuo to give the title compound (1.26 g, 100% yield) as yellow oil. ¹HNMR (400 MHz, CDCl₃) δ 7.42-7.28 (m, 5H), 5.13 (s, 2H), 5.01-4.97 (m,1H), 4.05-3.74 (m, 1H), 2.98 (s, 3H), 2.78 (s, 3H), 2.45 (m, 1H),2.34-2.21 (m, 1H), 2.11-2.06 (m, 1H), 2.02-1.97 (m, 1H), 1.74-1.67 (m,2H), 1.59-1.36 (m, 6H). LC-MS (ESI⁺) m/z 382.1 (M+H)⁺.

Step 8—Benzyl N-(2-cyanospiro[3.5]nonan-7-yl)-N-methyl-carbamate

To a solution of[7-[benzyloxycarbonyl(methyl)amino]spiro[3.5]nonan-2-yl]methanesulfonate (1.26 g, 3.30 mmol) in DML (10 mL) was added KCN (430mg, 6.61 mmol, 283 uL) and TBAI (122 mg, 330 umol). The reaction mixturewas heated to 120° C. for 16 hrs. On completion, the reaction mixturewas diluted with water (10 mL), and extracted with ethyl acetate (3×50mL). The combined organic layers were wash with brine (30 mL), driedover anhydrous sodium sulfate, filtered and the filtrate wasconcentrated in vacuo. The residue was purified by silica gelchromatography (petroleum ether/ethyl acetate=4/1) to give the titlecompound (570 mg, 55% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ7.45-7.28 (m, 5H), 5.13 (s, 2H), 4.07-3.73 (m, 1H), 3.06-2.98 (m, 1H),2.78 (s, 3H), 2.32-2.22 (m, 1H), 2.20-2.06 (m, 3H), 1.96-1.87 (m, 1H),1.82-1.78 (m, 1H), 1.62-1.59 (m, 2H), 1.54-1.36 (m, 4H). LC-MS (ESI⁺)m/z 313.1 (M+H)⁺.

Step 9—Benzyl N-[2-(aminomethyl)spiro[3.5]nonan-7-yl]-N-methyl-carbamate

To a solution of benzylN-(2-cyanospiro[3.5]nonan-7-yl)-N-methyl-carbamate (370 mg, 1.18 mmol)in MeOH (5 mL) was added Raney-Ni (101 mg, 1.18 mmol), NH₃.H₂O (3.37 g,31.7 mmol, 3.70 mL, 33% solution) under N₂. The suspension was degassedunder vacuum and purged with H₂ several times. The mixture was stirredunder H₂ (50 psi) at 25° C. for 4 hours. On completion, the reactionmixture was filtered and concentrated in vacuo to give the titlecompound (300 mg, 84% yield) as colorless oil. ¹H NMR (400 MHz, CDCl₃) δ7.47-7.29 (m, 5H), 5.15 (s, 2H), 4.89-4.50 (m, 2H), 4.04-3.78 (m, 1H),2.79 (s, 3H), 2.69 (d, J=7.2 Hz, 2H), 2.28-2.20 (m, 1H), 2.02-1.73 (m,6H), 1.48-1.31 (m, 6H); LC-MS (ESI⁺) m/z 317.1 (M+H)⁺.

2-(((((2S,4s,7S)-7-((tert-butoxycarbonyl)(methyl)amino)spiro[3.5]nonan-2-yl)methyl)-12-azaneyl)carbonyl)benzoicacid (Intermediate BCO) and2-(((((2R,4r,7R)-7-((tert-butoxycarbonyl)(methyl)amino)spiro[3.5]nonan-2-yl)methyl)-12-azaneyl)carbonyl)benzoicacid (Intermediate BCP)

Step 1—Tert-butyl N-(2-hydroxyspiro[3.5]nonan-7-yl)-N-methyl-carbamate

To a solution of tert-butylN-methyl-N-(2-oxospiro[3.5]nonan-7-yl)carbamate (12.0 g, 44.8 mmol,synthesized via Steps 1-5 of Intermediate ANJ) in a mixed solvents ofTHF (100 mL) and MeOH (30 mL) was added NaBH₄ (1.87 g, 49.3 mmol) at 0°C. The reaction mixture was stirred at 0° C. for 1 hour. On completion,the reaction mixture was quenched with sat. aq. NH₄Cl (30 mL), dilutedwith water (100 mL) and extracted with EA (3×200 mL). The combinedorganic layers were washed with brine (2×60 mL), dried over Na₂SO₄,filtered and concentrated in vacuo to give the title compound (11.5 g,95% yield) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 4.38-4.20 (m, 1H),4.03-3.52 (m, 1H), 2.70 (s, 3H), 2.39-2.25 (m, 1H), 2.20-2.08 (m, 1H),1.74-1.62 (m, 4H), 1.61-1.49 (m, 4H), 1.49-1.38 (m, 12H).

Step2—[7-[Tert-butoxycarbonyl(methyl)amino]spiro[3.5]nonan-2-yl]methanesulfonate

To a solution of tert-butylN-(2-hydroxyspiro[3.5]nonan-7-yl)-N-methyl-carbamate (15.5 g, 57.5 mmol)and TEA (8.73 g, 86.3 mmol) in DCM (150 mL) was added MsCl (7.91 g, 69.0mmol) at 0° C. The reaction mixture was stirred at 0-20° C. for 1 hour.On completion, the reaction mixture was diluted with water (100 mL) andextracted with DCM (3×100 mL). The combined organic layers were washedwith brine (2×60 mL), dried over Na₂SO₄, filtered and concentrated invacuo to give the title compound (19.0 g, 95% yield) as yellow oil. ¹HNMR (400 MHz, CDCl₃) δ 5.03-4.96 (m, 1H), 4.00-3.59 (m, 1H), 2.98 (s,3H), 2.70 (s, 3H), 2.53-2.40 (m, 1H), 2.33-2.21 (m, 1H), 2.17-1.93 (m,2H), 1.75-1.66 (m, 2H), 1.61-1.47 (m, 4H), 1.46 (s, 9H), 1.44-1.34 (m,2H).

Step 3—Tert-butyl N-(2-cyanospiro[3.5]nonan-7-yl)-N-methyl-carbamate

To a solution of[7-[tert-butoxycarbonyl(methyl)amino]spiro[3.5]nonan-2-yl]methanesulfonate(19.0 g, 54.6 mmol) and KI (13.6 g, 82.0 mmol) in DMSO (200 mL) wasadded NaCN (4.02 g, 82.0 mmol) at 25° C. The reaction mixture wasstirred at 100° C. for 48 hours. On completion, the reaction mixture waspoured into water (400 mL), and extracted with EA (3×180 mL). Thecombined organic layers were washed with brine (2×100 mL), dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bysilica gel chromatography (PE:EA=20:1) to give the title compound (9.90g, 65% yield) as white solid. ¹H NMR (400 MHz, CDCl₃) δ 4.05-3.51 (m,1H), 3.04-2.97 (m, 1H), 2.69 (s, 3H), 2.31-2.21 (m, 1H), 2.17-2.07 (m,3H), 1.94-1.84 (m, 1H), 1.82-1.72 (m, 1H), 1.60-1.50 (m, 2H), 1.50-1.46(m, 1H), 1.45 (s, 9H), 1.44-1.34 (m, 3H).

Step 4—Tert-butylN-[2-(aminomethyl)spiro[3.5]nonan-7-yl]-N-methyl-carbamate

To a solution of tert-butylN-(2-cyanospiro[3.5]nonan-7-yl)-N-methyl-carbamate (10.5 g, 37.7 mmol)and NH₃H₂O (36.4 g, 259 mmol, 40 mL) in MeOH (100 mL) was added Raney-Ni(969 mg, 11.3 mmol). The reaction mixture was stirred at 25° C. for 16hours under H₂ (50 psi). On completion, the reaction mixture wasfiltered and the filtrate was concentrated in vacuo to give the titlecompound (10.1 g, 94% yield) as yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ3.88-3.56 (m, 1H), 2.62 (s, 3H), 2.55-2.51 (m, 2H), 2.26-2.04 (m, 1H),1.95-1.74 (m, 2H), 1.72-1.63 (m, 1H), 1.62-1.40 (m, 4H), 1.38 (s, 9H),1.37-1.22 (m, 5H).

Step 5—Tert-butylN-[2-[(1,3-dioxoisoindolin-2-yl)methyl]spiro[3.5]nonan-7-yl]-N-methyl-carbamate

A mixture of tert-butylN-[2-(aminomethyl)spiro[3.5]nonan-7-yl]-N-methyl-carbamate (9.80 g, 34.7mmol) and isobenzofuran-1,3-dione (6.17 g, 41.6 mmol, CAS #85-44-9) intoluene (100 mL) was stirred at 110° C. for 12 hours. On completion, thereaction mixture was concentrated in vacuo. The residue was purified bysilica gel chromatography (PE:EA=20:1) to give the title compound (11.6g, 80% yield) as white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.84 (dd, J=3.2,5.6 Hz, 2H), 7.72 (dd, J=3.2, 5.6 Hz, 2H), 3.98-3.53 (m, 3H), 2.73-2.57(m, 4H), 2.00-1.89 (m, 1H), 1.85-1.75 (m, 2H), 1.73-1.64 (m, 1H),1.64-1.59 (m, 1H), 1.59-1.46 (m, 4H), 1.45 (s, 9H), 1.43-1.34 (m, 3H).

Step6—2-(((((2S,4s,7S)-7-((tert-butoxycarbonyl)(methyl)amino)spiro[3.5]nonan-2-yl)methyl)-12-azaneyl)carbonyl)benzoicacid (Intermediate BCO) and2-(((((2R,4r,7R)-7-((tert-butoxycarbonyl)(methyl)amino)spiro[3.5]nonan-2-yl)methyl)-12-azaneyl)carbonyl)benzoicacid

Racemic tert-butylN-[2-[(1,3-dioxoisoindolin-2-yl)methyl]spiro[3.5]nonan-7-yl]-N-methyl-carbamatewas separated by SFC ((column: DAICEL CHIRALCEL OJ-H (250 mm*30 mm, 5um); mobile phase: [0.1% NH₃.H₂O ETOH]) to give the two titlecompound._The first peak2-(((((2S,4s,7S)-7-((tert-butoxycarbonyl)(methyl)amino)spiro[3.5]nonan-2-yl)methyl)-12-azaneyl)carbonyl)benzoicacid (4.80 g, 96% yield, 99% ee) was obtained as colorless gum. ¹H NMR(400 MHz, CDCl₃) δ 7.84 (dd, J=3.2, 5.6 Hz, 2H), 7.72 (dd, J=3.2, 5.6Hz, 2H), 3.97-3.62 (m, 3H), 2.75-2.57 (m, 4H), 2.00-1.90 (m, 1H),1.86-1.74 (m, 2H), 1.72-1.64 (m, 1H), 1.63-1.54 (m, 2H), 1.54-1.46 (m,3H), 1.45 (s, 9H), 1.43-1.33 (m, 3H); LC-MS (ESI⁺) m/z 357.2 (M+H−56)⁺.The second peak2-(((((2R,4r,7R)-7-((tert-butoxycarbonyl)(methyl)amino)spiro[3.5]nonan-2-yl)methyl)-12-azaneyl)carbonyl)benzoicacid (4.90 g, 97% yield, 96.4% ee) was obtained as colorless gum. ¹H NMR(400 MHz, CDCl₃) δ 7.85 (dd, J=3.2, 5.6 Hz, 2H), 7.72 (dd, 0.7=3.2, 5.6Hz, 2H), 3.94-3.62 (m, 3H), 2.76-2.55 (m, 4H), 2.01-1.90 (m, 1H),1.86-1.74 (m, 2H), 1.72-1.65 (m, 1H), 1.64-1.59 (m, 1H), 1.55-1.47 (m,3H), 1.45 (s, 9H), 1.44-1.32 (m, 4H); LC-MS (ESI⁺) m/z 357.2 (M+H−56)⁺.Stereochemistry was assigned arbitrarily.

Tert-butyl N-[2-(aminomethyl)spiro[3.5]nonan-7-yl]-N-methyl-carbamate(Intermediate BCQ)

To a solution of tert-butylN-[2-[(1,3-dioxoisoindolin-2-yl)methyl]spiro[3.5]nonan-7-yl]-N-methyl-carbamate(450 mg, 1.09 mmol, Intermediate BCO) in EtOH (4 mL) was added N₂H₄H₂O(222 mg, 4.36 mmol). The reaction mixture was stirred at 80° C. for 2hours. On completion, the reaction mixture was concentrated in vacuo.The residue was diluted with DCM (100 mL) and filtered in vacuo. Thefiltrate was concentrated in vacuo to give the title compound (290 mg,94% yield) as colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 2.69 (s, 3H),2.67 (s, 1H), 2.23 (m, 1H), 1.95 (m, 1H), 1.88-1.74 (m, 2H), 1.64-1.46(m, 4H), 1.45 (s, 9H), 1.44-1.23 (m, 8H).

4-Bromo-3-methyl-1-(2-trimethylsilylethoxymethyl)benzimidazol-2-one(Intermediate BED)

To a mixture of 4-bromo-3-methyl-1H-benzimidazol-2-one (50.0 g, 220mmol, synthesized via Steps 1-3 of Intermediate HP) in DMF (500 mL) wasadded NaH (13.2 g, 330 mmol, 60% dispersion in mineral oil) at 0° C. Thereaction mixture was stirred for 30 minutes. Then SEMCl (44.0 g, 264mmol) was added dropwise at 0° C. and the reaction mixture was stirredfor 16 hours. On completion, the mixture was poured into water (500 mL).The mixture was extracted with DCM (3×200 mL) and the combined organiclayer was dried over by Na₂SO₄. The mixture was filtrated and thefiltrate was concentrated in vacuo. The residue was purified by columnchromatography (petroleum ether/ethyl acetate=20/l) to give the titlecompound (60.0 g, 76% yield) as yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ7.34-7.21 (m, 2H), 7.01-6.97 (m, 1H), 5.24 (s, 2H), 3.61 (s, 3H),3.55-3.51 (m, 2H), 0.85-0.81 (m, 2H), 0.07 (s, 9H).

3-[3-Methyl-4-[[7-(methylamino)spiro[3.5]nonan-2-yl]methylamino]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate BJI)

Step 1 Tert-butylN-methyl-N-[2-[[(3-methyl-2-oxo-1H-benzimidazol-4-yl)amino]methyl]spiro[3.5]nonan-7-yl]carbamate

To a solution of tert-butylN-methyl-N-[2-[[[3-methyl-2-oxo-1-(2-trimethylsilylethoxymethyl)benzimidazol-4-yl]amino]methyl]spiro[3.5]nonan-7-yl]carbamate (100 mg,178 umol, synthesized via Step 1 of Intermediate BKC) in THF (1 mL) wasadded TBAF (522 mg, 2.00 mmol) at 25° C. The mixture was stirred at25-80° C. for 12 hrs. On completion, the reaction mixture wasconcentrated in vacuo to give a residue. Then the residue was dilutedwith 15 mL H₂O and extracted with EA (3×5 mL). The combined organiclayers were washed with brine (2×5 mL), dried over by Na₂SO₄, filteredand the filtrate was concentrated in vacuo to give the title compound(80.0 mg, 93% yield, 90% purity) as a brown solid. LC-MS (ESI+) m/z429.3 (M+H)⁺.

Step 2—Tert-butylN-[2-[[[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-4-yl]amino]methyl]spiro[3.5]nonan-7-yl]-N-methyl-carbamate

To a solution of tert-butylN-methyl-N-[2-[[(3-methyl-2-oxo-1H-benzimidazol-4-yl)amino]methyl]spiro[3.5]nonan-7-yl]carbamate (80.0 mg, 168 umol) in THF (1.5 mL) wasadded t-BuOK (37.7 mg, 336 umol) at 0° C. The mixture was stirred at0-25° C. for 0.5 hr. Then [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl] trifluoromethane sulfonate (96.0 mg, 252umol, Intermediate IQ) was added to above mixture at 0° C. The reactionmixture was stirred at 0-25° C. for 2.5 hrs. On completion, the reactionmixture was concentrated in vacuo to give a residue. Then the mixturewas diluted with 15 mL H₂O and extracted with EA (3×5 mL). The combinedorganic layers were washed with brine (2×5 mL), dried over by Na₂SO₄,filtered and the filtrate was concentrated in vacuo. The residue waspurified by reverse phase (0.1% FA condition) to give the title compound(70.0 mg, 63% yield) as a blue solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.20(d, J=8.4 Hz, 2H), 6.85 (d, J=8.4 Hz, 2H), 6.80 (t, J=8.4 Hz, 1H), 6.40(d, J=8.4 Hz, 2H), 5.44 (dd, J=4.4, 12.4 Hz, 1H), 4.91 (t, J=5.2 Hz,1H), 4.86-4.71 (m, 2H), 3.72 (s, 3H), 3.60 (s, 3H), 3.07 (t, J=6.4 Hz,3H), 2.83-2.66 (m, 4H), 2.63 (s, 3H), 2.02-1.95 (m, 2H), 1.85-1.75 (m,2H), 1.65-1.61 (m, 1H), 1.56-1.42 (m, 6H), 1.38 (s, 9H), 1.35-1.26 (m,2H); LC-MS (ESI+) m/z 660.4 (M+H)⁺.

Step3—3-[3-Methyl-4-[[7-(methylamino)spiro[3.5]nonan-2-yl]methylamino]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[2-[[[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-4-yl]amino]methyl]spiro[3.5]nonan-7-yl]-N-methyl-carbamate(65.0 mg, 98.5 umol) in TFA (0.8 mL) was added TfOH (552 mg, 3.68 mmol)at 25° C. The mixture was stirred at 65° C. for 3 hrs. On completion,the reaction mixture was concentrated in vacuo. Then the mixture waslyophilized. The residue was purified by reverse phase (0.1% FAcondition) to give the title compound (40.0 mg, 92% yield) as a bluesolid. LC-MS (ESI+) m/z 440.2 (M+H)⁺.

3-[4-(2,7-diazaspiro[3.5]nonan-2-yl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate BIL)

Step 1—Tert-butyl2-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate

To a solution of3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (500mg, 1.48 mmol, Intermediate HP),tert-butyl2,7-diazaspiro[3.5]nonane-7-carboxylate (501 mg, 2.22 mmol,CAS #896464-16-7) and 4 Å molecular sieve (500 mg) in toluene (10.0 mL)was added[2-(2-aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane(229 mg, 295 umol), RuPhos (138 mg, 295 umol) and LiHMDS (1.00 M, 7.39mL) under N₂. The mixture was stirred at 80° C. for 6 hrs under N₂. Oncompletion, the mixture was adjust to pH=6 with FA. The mixture was thenfiltered and concentrated in vacuo. The mixture was diluted with H₂O (30mL) and extracted with EA (3×30 mL). The organic layers were washed withbrine (2×20 mL), dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo. The mixture was purified by reverse phase (0.1% FA) to givethe title compound (300 mg, 41% yield) as yellow solid. ¹H NMR (400 MHz,CDCl₃) δ 8.26 (s, 1H), 6.99 (t, J=8.0 Hz, 1H), 6.70 (d, J=8.0 Hz, 1H),6.47 (d, J=8.0 Hz, 1H), 5.25-5.10 (m, 1H), 3.72 (s, 3H), 3.66-3.60 (m,4H), 3.45-3.38 (m, 4H), 2.98-2.89 (m, 1H), 2.88-2.78 (m, 1H), 2.77-2.66(m, 1H), 2.28-2.17 (m, 1H), 1.85-1.79 (m, 4H), 1.48 (s, 9H); LC-MS (ESL)m/z 484.1 (M+H)⁺.

Step2—3-[4-(2,7-Diazaspiro[3.5]nonan-2-yl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl2-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate(100 mg, 206 umol) in DCM (3.00 mL) was added TFA (770 mg, 6.75 mmol).The mixture was stirred at 15° C. for 0.5 hr. On completion, the mixturewas concentrated in vacuo to give the title compound (100 mg, 97% yield,TFA) as yellow oil. LC-MS (ESL) m/z 384.2 (M+H)⁺.

2-(Trifluoromethyl)pyrimidine-4-carboxylic acid (Intermediate BIR)

Step 1—Methyl 2-(trifluoromethyl)pyrimidine-4-carboxylate

To a solution of 4-chloro-2-(trifluoromethyl)pyrimidine (100 mg, 547umol, CAS #1514-96-1) in MeOH (3 mL) was added Pd(dppf)Cl₂ (40.1 mg,54.8 umol) and TEA (166 mg, 1.64 mmol, 228 uL) under N₂ atmosphere. Thesuspension was degassed and purged with CO for 3 times. The mixture wasstirred under CO (50 Psi.) at 80° C. for 16 hrs. On completion, thereaction mixture was filtered and the filtrate concentrated in vacuo togive a residue. The residue was purified by column chromatography (SiO₂,petroleum ether/ethyl acetate=0/1 to 10/1, PE:EA=5:1, Rf=0.24) to givethe title compound (100 mg, 88% yield) as a white solid. ¹H NMR (400MHz, CDCl₃-d) δ 9.17 (d, J=5.2 Hz, 1H), 8.20 (d, J=4.8 Hz, 1H), 4.08 (s,3H).

Step 2—2-(Trifluoromethyl)pyrimidine-4-carboxylic acid

To a solution of methyl 2-(trifluoromethyl)pyrimidine-4-carboxylate(70.0 mg, 339 umol) in MeOH (4.00 mL) and H₂O (0.40 mL) was addedLiOH.H₂O (42.7 mg, 1.02 mmol). The mixture was stirred at 20° C. for 2hrs. On completion, the reaction mixture was concentrated in vacuo toremove MeOH, then acid by addition 1 N HCl until the pH=3-4, thenextracted with EA (3×5 mL). The combined organic layer was washed withbrine (2×10 mL), dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo to give the title compound (45.0 mg, 68% yield) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.29 (d, J=5.2 Hz, 1H), 8.26 (d,J=4.8 Hz, 1H).

N-[2-(4-formylcyclohexyl)-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]-2-(trifluoromethyl)pyrimidine-4-carboxamide (Intermediate BJJ)

Step1—N-[2-[4-(hydroxymethyl)cyclohexyl]-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]-2-(trifluoromethyl)pyrimidine-4-carboxamide

To a solution of2-[6-amino-2-[4-(hydroxymethyl)cyclohexyl]-1,3-benzothiazol-5-yl]propan-2-ol(40.0 mg, 112 umol, Intermediate BHD) and2-(trifluoromethyl)pyrimidine-4-carboxylic acid (25.3 mg, 112 umol,Intermediate BIR) in DMF (0.5 mL) was added HATU (55.5 mg, 146 umol) andDIEA (29.0 mg, 224 umol). The reaction mixture was stirred 25° C. for 2hours. On completion, the reaction mixture was filtered. The filtratewas purified by reverse phase (0.1% FA) to give the title compound (48.0mg, 86% yield) as white solid. ¹H NMR (400 MHz, CDCl₃) δ 12.49 (s, 1H),9.13 (d, J=5.2 Hz, 1H), 9.10 (s, 1H), 8.35 (d, J=5.2 Hz, 1H), 7.91 (s,1H), 3.47 (d, J=5.6 Hz, 2H), 2.98 (m, 1H), 2.27-2.20 (m, 2H), 2.18 (s,1H), 1.96-1.90 (m, 2H), 1.74 (s, 6H), 1.64 (m, 2H), 1.58-1.53 (m, 1H),1.17-1.07 (m, 2H).

Step2—N-[2-(4-formylcyclohexyl)-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]-2-(trifluoromethyl)pyrimidine-4-carboxamide

To a solution ofN-[2-[4-(hydroxymethyl)cyclohexyl]-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]-2-(trifluoromethyl)pyrimidine-4-carboxamide(50.0 mg, 101 umol) in DCM (0.5 mL) was added DMP (55.7 mg, 131 umol).The reaction mixture was stirred at 25° C. for 1 hour. The reactionmixture was quenched with sat. aq. Na₂S₂O₃ (1 mL), then added sat. aq.NaHCO₃ until the pH=7-8. On completion, the reaction mixture was dilutedwith water (10 mL), then extracted with DCM (3×10 mL). The combinedorganic layers was washed with brine (2×10 mL), dried over Na₂SO₄,filtered and concentrated in vacuo to give the title compound (42.0 mg,84% yield) was obtained as yellow solid. ¹H NMR (400 MHz, DMSO-d₆)512.74 (s, 1H), 9.63 (s, 1H), 9.38 (d, J=5.2 Hz, 1H), 9.09 (s, 1H), 8.45(d, J=5.2 Hz, 1H), 7.92 (s, 1H), 6.23 (s, 1H), 3.13-3.06 (m, 1H),2.42-2.38 (m, 1H), 2.25-2.20 (m, 2H), 2.10-2.04 (m, 2H), 1.72-1.67 (m,1H), 1.64 (s, 6H), 1.63-1.60 (m, 1H), 1.46-1.36 (m, 2H).

6-Bromo-5-methoxy-2-methylsulfonyl-1,3-benzothiazole (Intermediate BJM)

Step 1—5-Methoxy-2-methylsulfanyl-1,3-benzothiazole

To a mixture of 5-methoxy-1,3-benzothiazole-2-thiol (3.80 g, 19.2 mmol,CAS #55690-60-3) in DMF (50.0 mL) was added K₂CO₃ (5.32 g, 38.5 mmol)and CH₃I (4.10 g, 28.8 mmol) at 0° C. The mixture was stirred at 20° C.for 0.5 hour. On completion, the mixture was poured into the water (120mL) and the aqueous phase was extracted with ethyl acetate (2×50 mL).The combined organic phase was washed with brine (2×50 mL), dried withanhydrous Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound (4.00 g, 98% yield) as brown oil. ¹H NMR (400 MHz, CDCl₃) δ7.60 (d, J=8.8 Hz, 1H), 7.40 (d, J=2.4 Hz, 1H), 6.94 (dd, J=2.4, 8.8 Hz,1H), 3.87 (s, 3H), 2.78 (s, 3H).

Step 2—6-Bromo-5-methoxy-2-methylsulfanyl-1,3-benzothiazole

To a mixture of 5-methoxy-2-methylsulfanyl-1,3-benzothiazole (3.8 g,17.9 mmol) in CH₃CN (40 mL) was added NBS (3.20 g, 17.9 mmol) at 0° C.The mixture was stirred at 0° C. for 0.5 hour. On completion, themixture was concentrated at 45° C. The residue was purified byre-crystallization from EA (5 mL) and MTBA (15 mL) at 60° C. to give thetitle compound (2.00 g, 38% yield) as white solid. ¹H NMR (400 MHz,CDCl₃) δ 7.81 (s, 1H), 7.32 (s, 1H), 3.88 (s, 3H), 2.70 (s, 3H).

Step 3—6-Bromo-5-methoxy-2-methylsulfonyl-1,3-benzothiazole

To a mixture of 6-bromo-5-methoxy-2-methylsulfanyl-1,3-benzothiazole(2.00 g, 6.89 mmol) in DCM (20 mL) was added m-CPBA (2.80 g, 13.7 mmol,85% solution). The reaction mixture was stirred at 25° C. for 0.5 hour.On completion, the mixture was poured into the water (200 mL), andextracted with DCM (2×150 mL). The combined organic phase was washedwith brine (2×200 mL), dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuo at 45° C. to give the title compound (2.70 g, 80%yield) as white solid, ¹H NMR (400 MHz, CDCl₃) δ 8.10 (s, 1H), 7.55 (s,1H), 3.93 (s, 3H), 3.32 (s, 3H).

[1-(6-Bromo-5-methoxy-1,3-benzothiazol-2-yl)-4-piperidyl]methanol(Intermediate BJN)

To a solution of 6-bromo-5-methoxy-2-methylsulfonyl-1,3-benzothiazole(2.7 g, 8.38 mmol, Intermediate BJM) and 4-piperidylmethanol (1.06 g,9.22 mmol, CAS #6457-49-4) in DMF (30 mL) was added K₂CO₃ (2.32 g, 16.7mmol), the mixture was stirred at 60° C. for 16 hrs. On completion, themixture was diluted with H₂O (180 mL), then extracted with EA (3×50 mL).The organic layers were washed with brine (3×50 mL) and dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The mixture waspurified by silica gel column (PE:EA=2:3) to give the title compound(1.70 g, 56% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.94 (s,1H), 7.17 (s, 1H), 4.54 (t, J=5.2 Hz, 1H), 4.05-3.95 (m, 2H), 3.84 (s,3H), 3.31-3.27 (m, 2H), 3.18-3.08 (m, 2H), 1.83-1.73 (m, 2H), 1.72-1.60(m, 1H), 1.28-1.11 (m, 2H), LC-MS (ESI⁺) m/z 359.0 (M+H)⁺.

N-[2-(4-formyl-1-piperidyl)-5-methoxy-1,3-benzothiazol-6-yl]pyrimidine-4-carboxamide(Intermediate BJO)

Step1—N-[2-[4-(hydroxymethyl)-1-piperidyl]-5-methoxy-1,3-benzothiazol-6-yl]pyrimidine-4-carboxamide

To a solution of[1-(6-bromo-5-methoxy-1,3-benzothiazol-2-yl)-4-piperidyl]methanol (500mg, 1.40 mmol, Intermediate BJN), pyrimidine-4-carboxamide (206 mg, 1.68mmol, CAS #28648-86-4) in dioxane (10 mL) was added Pd₂(dba)₃ (128 mg,139 umol), Xantphos (161 mg, 279 umol) and Cs₂CO₃ (911 mg, 2.80 mmol).The mixture was stirred at 100° C. for 60 hrs under N₂. On completion,the mixture was filtered and concentrated in vacuo. The mixture waspurified by prep-HPLC (reverse phase: 0.1% FA) to give the titlecompound (190 mg, 33% yield) as yellow solid. Ti NMR (400 MHz, DMSO-d₆)δ 10.40 (s, 1H), 9.43 (s, 1H), 9.16 (d, J=5.2 Hz, 1H), 8.73 (s, 1H),8.17 (d, J=5.2 Hz, 1H), 7.28 (d, J=7.2 Hz, 1H), 4.36-4.28 (m, 1H),4.09-4.00 (m, 2H), 3.98 (s, 3H), 3.33-3.26 (m, 1H), 3.25-3.10 (m, 2H),1.88-1.61 (m, 3H), 1.47-1.16 (m, 2H), LC-MS (ESI⁺) m/z 400.1 (M+H)⁺.

Step2—N-[2-(4-formyl-1-piperidyl)-5-methoxy-1,3-benzothiazol-6-yl]pyrimidine-4-carboxamide

To a solution ofN-[2-[4-(hydroxymethyl)-1-piperidyl]-5-methoxy-1,3-benzothiazol-6-yl]pyrimidine-4-carboxamide(120 mg, 300 umol) in DCM (4.00 mL) was added DMP (191 mg, 450 umol) andNaHCO₃ (126 mg, 1.50 mmol). The mixture was stirred at 15° C. for 0.5hr. On completion, the mixture was diluted with DCM (20 mL) and quenchedwith saturated Na₂S₂O₃ (15 mL) and washed with saturated NaHCO₃ (2×15mL). The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The mixture was purified by prep-TLC (EA) to givethe title compound (30.0 mg, 25% yield) as yellow solid. LC-MS (ESI⁺)m/z 416.2 (M+H₂O+H)⁺.

2-[6-Amino-2-[4-(hydroxymethyl)-1-piperidyl]-1,3-benzothiazol-5-yl]propan-2-ol(Intermediate BJP)

Step 1—Methyl6-[(2,4-dimethoxyphenyl)methylamino]-2-[4-(hydroxymethyl)-1-piperidyl]-1,3-benzothiazole-5-carboxylate

A mixture of methyl6-bromo-2-[4-(hydroxymethyl)-1-piperidyl]-1,3-benzothiazole-5-carboxylate(550 mg, 1.43 mmol, Intermediate BCJ), (2,4-dimethoxyphenyl)methanamine(358 mg, 2.14 mmol, CAS #20781-20-8), Cs₂CO₃ (930 mg, 2.86 mmol),Xantphos (165 mg, 285 umol) and Pd₂(dba)₃ (131 mg, 143 umol) in dioxane(10 mL) was de-gassed and heated at 100° C. for 12 hrs. On completion,the mixture was filtered and the filtrate was concentrated in vacuo. Theresidue was purified by silica gel chromatography (SiO₂) to give thetitle compound (290 mg, 43% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 7.92-7.86 (m, 1H), 7.81 (s, 1H), 7.22-7.15 (m, 2H), 6.59 (d,J=2.4 Hz, 1H), 6.47 (dd, J=2.4, 8.4 Hz, 1H), 4.56-4.50 (m, 1H), 4.28 (d,J=4.0 Hz, 2H), 3.85 (s, 2H), 3.81 (s, 3H), 3.79 (s, 3H), 3.74 (s, 3H),3.28 (d, J=6.0 Hz, 2H), 3.18-3.07 (m, 2H), 1.82-1.74 (m, 2H), 1.69-1.62(m, 1H), 1.27-1.19 (m, 2H).

Step 2—Methyl6-amino-2-[4-(hydroxymethyl)-1-piperidyl]-1,3-benzothiazole-5-carboxylate

A solution of methyl6-[(2,4-dimethoxyphenyl)methylamino]-2-[4-(hydroxymethyl)-1-piperidyl]-1,3-benzothiazole-5-carboxylate(290 mg, 615 umol) in TFA (5 mL) was stirred at 20° C. for 3 hrs. Thenthe mixture was concentrated in vacuo. The residue was then dissolved inTHF (5 mL) and K₂CO₃ (255 mg, 1.84 mmol) was added and the reactionmixture was stirred at 20° C. for 2 hrs. On completion, the mixture wasdiluted with water (50 mL), and extracted with EA (2×50 mL). The organiclayer was concentrated in vacuo and the residue was purified by reversephase (0.1% FA condition) to give the title compound (150 mg, 76% yield)as yellow solid. LC-MS (ESI⁺) m/z 322.1 (M+H)⁺.

Step3—2-[6-Amino-2-[4-(hydroxymethyl)-1-piperidyl]-1,3-benzothiazol-5-yl]propan-2-ol

To a solution of methyl6-amino-2-[4-(hydroxymethyl)-1-piperidyl]-1,3-benzothiazole-5-carboxylate(100 mg, 311 umol) in THF (20 mL) was added MeMgBr (3 M, 1.04 mL)dropwise. Then the reaction mixture was stirred at 0° C. for 2 hrs. Oncompletion, the mixture was quenched with water (10 mL), filtered andthe filtrate was concentrated in vacuo. The residue was purified byreverse phase (0.1% FA condition) to give the title compound (65.0 mg,65% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.15 (s, 1H),6.91 (s, 1H), 5.52-4.97 (m, 2H), 4.50 (s, 1H), 3.91 (d, J=12.8 Hz, 2H),3.26 (d, J=6.0 Hz, 2H), 3.09-2.95 (m, 2H), 1.76-1.68 (m, 2H), 1.67-1.57(m, 1H), 1.52 (s, 6H), 1.28-1.05 (m, 2H).

N-[2-(4-formyl-1-piperidyl)-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]pyrimidine-4-carboxamide(Intermediate BJQ)

Step1—N-[5-(1-hydroxy-1-methyl-ethyl)-2-[4-(hydroxymethyl)-1-piperidyl]-1,3-benzothiazol-6-yl]pyrimidine-4-carboxamide

To a solution of2-[6-amino-2-[4-(hydroxymethyl)-1-piperidyl]-1,3-benzothiazol-5-yl]propan-2-ol(50.0 mg, 156 umol, Intermediate BJP) and pyrimidine-4-carboxylic acid(17.4 mg, 140 umol, CAS #31462-59-6) in DMF (1 mL) was added CMPI (47.7mg, 187 umol) and DIEA (60.3 mg, 467 umol). The reaction mixture wasstirred at 20° C. for 0.5 hr. On completion, the mixture was quenchedwith water (0.1 mL), and concentrated in vacuo. The residue was purifiedby reverse phase (0.1% FA condition) to give the title compound (50.0mg, 75% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.50 (s,1H), 9.38 (d, J=1.2 Hz, 1H), 9.14 (d, J=5.2 Hz, 1H), 8.80-8.68 (m, 1H),8.17 (dd, J=1.2, 5.2 Hz, 1H), 7.41 (s, 1H), 6.18 (s, 1H), 4.54 (t, J=5.2Hz, 1H), 4.08-3.98 (m, 2H), 3.28-3.26 (m, 2H), 3.18-3.08 (m, 2H),1.82-1.74 (m, 2H), 1.71-1.62 (m, 1H), 1.58 (s, 6H), 1.30-1.11 (m, 2H).

Step2—N-[2-(4-formyl-1-piperidyl)-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]pyrimidine-4-carboxamide

To a solution ofN-[5-(1-hydroxy-1-methyl-ethyl)-2-[4-(hydroxymethyl)-1-piperidyl]-1,3-benzothiazol-6-yl]pyrimidine-4-carboxamide (40.0 mg, 93.6 umol) and NaHCO₃ (39.3 mg,468 umol) in DCM (5 mL) was added DMP (59.5 mg, 140 umol). Then thereaction mixture was stirred at 20° C. for 2 hrs. On completion, themixture was quenched with sat. Na₂S₂O₃ (20 mL) and NaHCO₃ (20 mL),stirred for 10 min, then extracted with DCM (2×30 mL). The organic layerwas washed with brine (50 mL), dried in Na₂SO₄, filtered and thefiltrate was concentrated in vacuo to give the title compound (35.0 mg,88% yield) as a yellow solid. LC-MS (ESI⁺) m/z 444.2 (M+H₂O+H)⁺.

3-[4-(2,7-diazaspiro[3.5]nonan-7-yl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate BJR)

Step 1—Tert-butyl7-[3-methyl-2-oxo-1-(2-trimethylsilylethoxymethyl)benzimidazol-4-yl]-2,7-diazaspiro[3.5]nonane-2-carboxylate

To a mixture of4-bromo-3-methyl-1-(2-trimethylsilylethoxymethyl)benzimidazol-2-one(10.0 g, 28.0 mmol, Intermediate BED) and tert-butyl2,7-diazaspiro[3.5]nonane-2-carboxylate (8.23 g, 36.4 mmol) in dioxane(50 mL) was added Pd₂(dba)₃ (1.54 g, 1.68 mmol), RuPhos (783 mg, 1.68mmol) and t-BuONa (5.38 g, 55.9 mmol). The mixture was stirred at 80° C.for 16 hours. On completion, the reaction mixture was quenched with H₂O(2.0 mL) at 25° C., filtered and concentrated in vacuo to give aresidue. The residue was purified by column chromatography (SiO₂,petroleum ether/ethyl acetate=10/1 to 3/1) to give the title compound(7.9 g, 56% yield) as yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.06-6.99(m, 1H), 6.97-6.93 (m, 1H), 6.88 (d, J=8.0 Hz, 1H), 5.29 (s, 2H), 3.75(d, J=4.8 Hz, 2H), 3.73 (s, 3H), 3.68 (s, 2H), 3.64-3.57 (m, 2H), 3.09(d, J=10.0 Hz, 2H), 2.79-2.58 (m, 2H), 1.95 (s, 4H), 1.47 (s, 9H),0.96-0.89 (m, 2H), −0.03 (s, 9H); LC-MS (ESI+) m/z 503.4 (M+H)⁺.

Step 2—Tert-butyl7-(3-methyl-2-oxo-1H-benzimidazol-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

To a mixture of tert-butyl7-[3-methyl-2-oxo-1-(2-trimethylsilylethoxymethyl)benzimidazol-4-yl]-2,7-diazaspiro[3.5]nonane-2-carboxylate(7.4 g, 14.7 mmol) in THF (37.0 mL) was added TBAF (19.2 g, 73.6 mmol)at 25° C. The mixture was stirred at 85° C. for 16 hours. On completion,the mixture was concentrated in vacuo to give a residue. The residue wasdiluted with H₂O (200 mL) and then extracted with EA (3×100 mL). Thecombined organic phase was dried over Na₂SO₄, filtered and concentratedin vacuo to give a residue. The residue was purified by reverse phase(FA condition) to afford the title compound (3.5 g, 64% yield) as yellowsolid. ¹H NMR (400 MHz, CDCl₃) δ 9.40 (s, 1H), 7.01-6.95 (m, 1H),6.89-6.81 (m, 2H), 3.74 (s, 5H), 3.68 (s, 2H), 3.10 (d, J=7.8 Hz, 2H),2.69 (s, 2H), 1.95 (s, 4H), 1.47 (s, 9H); LC-MS (ESI+) m/z 373.2 (M+H)⁺.

Step 3—Tert-butyl7-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-4-yl]-2,7-diazaspiro[3.5]nonane-2-carboxylate

To a mixture of tert-butyl7-(3-methyl-2-oxo-1H-benzimidazol-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate(3.0 g, 8.05 mmol) in THF (50 mL) was added t-BuOK (1.81 g, 16.1 mmol)at −10° C. under N₂. The mixture was stirred at −10° C. for 1.0 hour.Then, a solution of [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]trifluoromethanesulfonate (6.14 g, 16.1 mmol, Intermediate IQ) in THF(50 mL) was added dropwise at −10° C. for 30 mins. Then, the mixture wasstirred at 0° C. for 4.0 hours. On completion, the reaction mixture wasquenched with FA (6 mL) until the pH=2.0 at 0° C., and then concentratedin vacuo to give a residue. The residue was diluted with H₂O (100 mL)and extracted with EA (3×100 mL). The combined organic layers werewashed with brine (80 mL), dried over Na₂SO₄, filtered and concentratedin vacuo to give a residue. The residue was purified by reverse phase(FA condition) to give the title compound (3.5 g, 72% yield) as yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.21 (d, J=8.8 Hz, 2H), 6.93-6.87 (m,2H), 6.85 (d, J=8.8 Hz, 2H), 6.77 (d, J=6.2 Hz, 1H), 5.54-5.45 (m, 1H),4.85-4.72 (m, 2H), 3.72 (s, 3H), 3.71 (d, J=1.2 Hz, 1H), 3.62 (s, 3H),3.57 (s, 1H), 3.11-2.92 (m, 3H), 2.85-2.57 (m, 5H), 2.06-1.99 (m, 1H),1.86 (s, 4H), 1.39 (s, 9H); LC-MS (ESI+) m/z 604.3 (M+H)⁺.

Step4—3-[4-(2,7-diazaspiro[3.5]nonan-7-yl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

A mixture of tert-butyl7-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-4-yl]-2,7-diazaspiro[3.5]nonane-2-carboxylate(1.5 g, 2.48 mmol) in TFA (80 mL) and TfOH (10 mL) was stirred at 60° C.for 3 hours. On completion, the mixture was concentrated in vacuo togive the title compound (800 mg, 84% yield) as yellow oil. LC-MS (ESI+)m/z 384.2 (M+H)⁺.

Step 5—Tert-butyl7-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-2,7-diazaspiro[3.5]nonane-2-carboxylate

To a mixture of3-[4-(2,7-diazaspiro[3.5]nonan-7-yl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(800 mg, 2.09 mmol) in ACN (10.0 mL) was added TEA (1.06 g, 10.4 mmol,1.45 mL) and Boc₂O (910 mg, 4.17 mmol). The mixture was stirred at 0° C.for 2.0 hours. On completion, the mixture was concentrated in vacuo togive a residue. The residue was diluted with H₂O (100 mL) and thenextracted with EA (3×80 mL). The combined organic phase was dried overNa₂SO₄, filtered and the filtrate was concentrated in vacuo to give aresidue. The residue was purified by reverse phase (FA condition) toafford the title compound (850 mg, 84% yield) as yellow solid. ¹H NMR(400 MHz, CDCl₃) δ 8.08 (s, 1H), 7.05-6.95 (m, 1H), 6.89 (d, J=8.2 Hz,1H), 6.58 (d, J=7.2 Hz, 1H), 5.24-5.17 (m, 1H), 3.76 (s, 5H), 3.68 (s,2H), 3.15-3.04 (m, 2H), 2.99-2.90 (m, 1H), 2.88-2.63 (m, 4H), 2.27-2.17(m, 1H), 1.95 (s, 4H), 1.47 (s, 9H); LC-MS (ESI+) m/z 484.3 (M+H)⁺.

Step6—3-[4-(2,7-diazaspiro[3.5]nonan-7-yl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a mixture of tert-butyl7-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-2,7-diazaspiro[3.5]nonane-2-carboxylate(200 mg, 413 umol) in DCM (4.0 mL) was added TFA (47.1 mg, 413 umol,30.6 uL) at 25° C. The mixture was stirred at 25° C. for 2 hours. Oncompletion, the mixture was concentrated in vacuo to give the titlecompound (120 mg, 76% yield) as yellow oil. LC-MS (ESI+) m/z 384.3(M+H)⁺.

N-[2-(4-formylcyclohexyl)-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]pyrazine-2-carboxamide(Intermediate BJS)

Step 1N-[2-[4-(hydroxymethyl)cyclohexyl]-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]pyrazine-2-carboxamide

To a solution of2-[6-amino-2-[4-(hydroxymethyl)cyclohexyl]-1,3-benzothiazol-5-yl]propan-2-ol(300 mg, 936 umol, Intermediate BHD) in DMF (5.0 mL) was added CMPI (287mg, 1.12 mmol) and DIEA (604 mg, 4.68 mmol, 815 uL), and the reactionmixture was stirred at 15° C. for 30 mins. Then pyrazine-2-carboxylicacid (116 mg, 936 umol, CAS #98-97-5) was added to the mixture, and thereaction mixture was stirred at 15° C. for 12 hours. On completion, thereaction mixture was concentrated in vacuo to give a residue. Theresidue was purified by reverse phase (0.1% FA condition) to give thetitle compound (250 mg, 62% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 12.54 (s, 1H), 9.36 (d, J=1.2 Hz, 1H), 9.08-9.01 (m, 1H),8.93 (d, J=2.4 Hz, 1H), 8.80 (dd, J=1.6, 2.4 Hz, 1H), 7.91-7.84 (m, 1H),6.31 (s, 1H), 4.50 (t, J=5.2 Hz, 1H), 3.27 (t, J=5.6 Hz, 2H), 3.08-2.97(m, 1H), 2.22-2.10 (m, 2H), 1.91-1.83 (m, 2H), 1.62 (s, 6H), 1.60-1.50(m, 2H), 1.47-1.39 (m, 1H), 1.17-1.02 (m, 2H); LC-MS (ESI⁺) m/z 427.3(M+1)⁺.

Step 2N-[2-(4-formylcyclohexyl)-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]pyrazine-2-carboxamide

To a solution ofN-[2-[4-(hydroxymethyl)cyclohexyl]-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl] pyrazine-2-carboxamide (250 mg, 586 umol) in DCM (8.0 mL) wasadded DMP (298 mg, 703 umol), and the mixture was stirred at 15° C. for1 hour. On completion, the reaction mixture was quenched with Na₂S₂O₃(10 mL) and extracted with DCM (2×20 mL). The combined organic phase waswashed with NaHCO₃ and brine (2×15 mL), dried with anhydrous Na₂SO₄,filtered and concentrated in vacuo to give the title compound (240 mg,96% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.64 (s, 1H),9.63 (s, 1H), 9.52 (s, 1H), 9.32 (s, 1H), 9.08 (s, 1H), 7.91 (s, 1H),6.35 (s, 1H), 3.15-3.04 (m, 1H), 2.45-2.35 (m, 1H), 2.28-2.19 (m, 2H),2.12-2.02 (m, 2H), 1.74-1.65 (m, 2H), 1.64 (s, 6H), 1.47-1.35 (m, 2H).LC-MS (ESI⁺) m/z 425.1 (M+1)⁺.

N-[2-(4-formylcyclohexyl)-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]-6-methyl-pyrazine-2-carboxamide(Intermediate BJT)

Step 1N-[2-[4-(hydroxymethyl)cyclohexyl]-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]-6-methyl-pyrazine-2-carboxamide

To a solution of2-[6-amino-2-[4-(hydroxymethyl)cyclohexyl]-1,3-benzothiazol-5-yl]propan-2-ol(80.0 mg, 249 umol, Intermediate BHD), 6-methylpyrazine-2-carboxylicacid (34.5 mg, 249 umol, CAS #5521-61-9) in DMF (3.5 mL) was added DIEA(64.5 mg, 499 umol), HATU (142 mg, 374 umol) at 25° C. The mixture wasstirred at 25° C. for 1 hour. On completion, the mixture was purified byreverse phase flash (FA condition) to give the title compound (80.0 mg,65% yield, FA salt) as light yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ12.60 (s, 1H), 9.13 (s, 1H), 9.06 (s, 1H), 8.83 (s, 1H), 7.89 (s, 1H),6.20 (s, 1H), 5.76 (s, 1H), 4.45 (t, J=5.2 Hz, 1H), 3.27 (t, J=5.2 Hz,2H), 3.03 (tt, J=3.6, 12.0 Hz, 1H), 2.64 (s, 3H), 2.17 (dd, J=2.4, 13.6Hz, 2H), 1.88 (dd, J=2.6, 13.2 Hz, 2H), 1.64 (s, 6H), 1.60-1.50 (m, 2H),1.45-1.43 (m, 1H), 1.10 (dq, J=3.2, 12.6 Hz, 2H); LC-MS (ESI⁺) m/z 441.2(M+H)⁺.

Step2—N-[2-(4-formylcyclohexyl)-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]-6-methyl-pyrazine-2-carboxamide

To a solution ofN-[2-[4-(hydroxymethyl)cyclohexyl]-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]-6-methyl-pyrazine-2-carboxamide(70.0 mg, 126 umol) in DCM (2.5 mL) was added DMP (80.0 mg, 189 umol) at25° C. The mixture was stirred at 25° C. for 1 hour. On completion, thereaction was quenched with sat. aq. Na₂S₂O₃ (1 mL) and sat. aq. NaHCO₃(3 mL). The residue was diluted with water (10 mL), extracted with DCM(3×40 mL). The combined organic layer was dried over Na₂SO₄, filteredand concentrated in vacuo to give the title compound (55.0 mg, 99%yield) as light brown solid. LC-MS (ESI⁺) m/z 439.2 (M+H)⁺.

Methyl6-bromo-2-[3-(hydroxymethyl)azetidin-1-yl]-1,3-benzothiazole-5-carboxylate(Intermediate BFR)

Step 1—Methyl2-[3-(hydroxymethyl)azetidin-1-yl]-1,3-benzothiazole-5-carboxylate

A mixture of methyl 2-methylsulfonyl-1,3-benzothiazole-5-carboxylate(2.00 g, 7.37 mmol, synthesized via Steps 1-3 of Intermediate BCJ),azetidin-3-ylmethanol (706 mg, 8.11 mmol, CAS #928038-44-2) and K₂CO₃(2.04 g, 14.7 mmol) in DMF (20 mL) was stirred at 60° C. for 2 hours. Oncompletion, the reaction mixture was diluted with water (20 mL) andextracted with EA (3×20 mL). The combined organic layers was washed withbrine (2×20 mL), dried over Na₂SO₄, filtered and concentrated in vacuoto give the title compound (1.80 g, 87% yield) as white solid. ¹H NMR(400 MHz, CDCl₃) δ 8.17 (d, J=1.6 Hz, 1H), 7.70 (dd, J=1.6, 8.2 Hz, 1H),7.57 (d, J=8.4 Hz, 1H),4.21 (t, J=8.4 Hz, 2H), 3.96 (dd, J=5.2, 8.4 Hz,2H), 3.85 (s, 3H), 3.83 (d, J=6.0 Hz, 2H), 3.05-2.93 (m, 1H).

Step 2—Methyl6-bromo-2-[3-(hydroxymethyl)azetidin-1-yl]-1,3-benzothiazole-5-carboxylate

To a solution of methyl2-[3-(hydroxymethyl)azetidin-1-yl]-1,3-benzothiazole-5-carboxylate (1.50g, 5.39 mmol) in a mixed solution of DCM (6.0 mL), TFA (6.0 mL) andH₂SO₄ (3.0 mL) was added NBS (1.15 g, 6.47 mmol). The reaction mixturewas stirred at 0° C. for 12 hours. On completion, a solution of K₂CO₃(2.23 g, 16.17 mmol) in MeOH (1.0 mL) was added to the above mixture andstirred at 25° C. for 0.5 hour. After that, the reaction mixture wasdiluted with water (10 mL), then extracted with DCM (3×10 mL). Thecombined organic layer was washed with brine (3×10 mL), dried overNa₂SO₄, filtered and concentrated in vacuo to give a residue. Theresidue was purified by silica gel chromatography (PE/EA/DCM=1:1:0.1) togive the title compound (1.1 g, 57% yield) as brown solid. ¹H NMR (400MHz, CDCl₃) δ 8.01 (s, 1H), 7.86 (s, 1H), 4.29 (t, J=8.4 Hz, 2H), 4.03(m, 3H), 3.94 (s, 3H), 3.91 (d, J=5.6 Hz, 2H), 3.14-3.02 (m, 1H).

N-[2-(3-formylazetidin-1-yl)-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide(Intermediate BFS)

Step 1—Methyl2-[3-(hydroxymethyl)azetidin-1-yl]-6-[[6-(trifluoromethyl)pyridine-2-carbonyl]amino]-1,3-benzothiazole-5-carboxylate

A mixture of methyl6-bromo-2-[3-(hydroxymethyl)azetidin-1-yl]-1,3-benzothiazole-5-carboxylate(400 mg, 1.12 mmol, Intermediate BFR),6-(trifluoromethyl)pyridine-2-carboxamide (212 mg, 1.12 mmol,Intermediate ATI), Xantphos (129 mg, 223 umol), Pd₂(dba)₃ (102 mg, 111umol) and Cs₂CO₃ (729 mg, 2.24 mmol) in dioxane (8.0 mL) was stirred at80° C. for 12 hours. On completion, the reaction mixture was filteredand concentrated in vacuo to give a residue. The residue was purified bysilica gel chromatography (PE/EA=1:1) to give title compound (240 mg,45% yield) as brown solid. ¹H NMR (400 MHz, CDCl₃) δ 12.89 (s, 1H), 9.20(s, 1H), 8.42 (d, J=5.0 Hz, 1H), 8.24 (s, 1H), 8.04 (t, J=IF Hz, 1H),7.80 (d, J=7.6 Hz, 1H), 4.22 (t, J=8.4 Hz, 2H), 4.00-3.93 (m, 5H), 3.83(d, J=6.4 Hz, 2H), 3.07-2.93 (m, 1H).

Step2—N-[2-[3-(hydroxymethyl)azetidin-1-yl]-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

To a solution of methyl2-[3-(hydroxymethyl)azetidin-1-yl]-6-[[6-(trifluoromethyl)pyridine-2-carbonyl]amino]-1,3-benzothiazole-5-carboxylate (190 mg, 407 umol) in THF (2.0mL) was added MeMgBr (3 M, 1.36 mL) at 0° C. The reaction mixture wasstirred at 25° C. for 2 hours. On completion, the reaction mixture wasquenched with sat. aq. NH₄Cl (1.0 mL), diluted with water (5.0 mL), thenextracted with EA (3×5.0 mL). The combined organic layer was washed withbrine (2×5.0 mL), dried over Na₂SO₄, filtered and concentrated in vacuoto give the title compound (120 mg, 63% yield) as brown solid. ¹H NMR(400 MHz, CDCl₃) δ 12.29 (s, 1H), 8.94 (s, 1H), 8.49 (d, J=7.6 Hz, 1H),8.11 (t, J=IF Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.61 (s, 1H), 5.31 (s,2H), 4.28 (t, J=8.0 Hz, 2H), 4.01 (dd, J=5.6, 8.0 Hz, 2H), 3.91 (t,J=5.2 Hz, 2H), 3.13-3.00 (m, 1H), 1.76 (s, 6H).

Step3—N-[2-(3-formylazetidin-1-yl)-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

To a solution ofN-[2-[3-(hydroxymethyl)azetidin-1-yl]-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide(50.0 mg, 107 umol) in DCM (0.5 mL) was added DMP (59.1 mg, 139 umol).The reaction mixture was stirred at 25° C. for 2 hours. On completion,the reaction mixture was quenched with saturated aq. Na₂S₂O₃ (1.0 mL)and saturated aq. NaHCO₃ (1.0 mL). The reaction mixture was diluted withwater (5.0 mL), then extracted with DCM (3×5.0 mL). The combined organiclayer was washed with brine (2×5.0 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (40.0 mg, 80% yield) asbrown solid. ¹H NMR (400 MHz, CDCl₃) δ 12.24 (s, 1H), 9.88 (d, J=1.6 Hz,1H), 8.89 (s, 1H), 8.42 (d, J=7.6 Hz, 1H), 8.04 (t, J=8.0 Hz, 1H), 7.77(d, J=7.6 Hz, 1H), 7.55 (s, 1H), 4.37-4.24 (m, 4H), 3.66-3.55 (m, 1H),1.69 (s, 6H).

6-(Trifluoromethyl)pyrazine-2-carboxylic acid (Intermediate BGR)

Step 1—Methyl 6-(trifluoromethyl)pyrazine-2-carboxylate

A solution of 2-chloro-6-(trifluoromethyl)pyrazine (1.90 g, 10.4 mmol),Pd(dppf)Cl₂ (762 mg, 1.04 mmol) and TEA (10.5 g, 104 mmol) in MeOH (50mL) was stirred at 70° C. for 12 hrs under CO (50 Psi) atmosphere. Oncompletion, the mixture was concentrated in vacuo. The residue waspurified by silica gel chromatography (SiO₂) to give the title compound(1.90 g, 89% yield) as colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 9.52 (s,1H), 9.15 (s, 1H), 4.08 (s, 3H).

Step 2—6-(Trifluoromethyl)pyrazine-2-carboxylic acid

To a solution of methyl 6-(trifluoromethyl)pyrazine-2-carboxylate (300mg, 1.46 mmol) in a mixed solvent of H₂O (1 mL) and MeOH (5 mL) wasadded LiOH.H₂O (183 mg, 4.37 mmol). The reaction mixture was stirred at20° C. for 1 hr. On completion, the mixture was acidified with 1N HCl topH=3-4, then dried in vacuo to give the title compound (260 mg, 93%yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.38 (s, 1H), 9.24(s, 1H).

N-[2-(4-formylcyclohexyl)-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]-6-(trifluoromethyl)pyrazine-2-carboxamide (Intermediate BJU)

Step1—N-[2-[4-(hydroxymethyl)cyclohexyl]-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]-6-(trifluoromethyl)pyrazine-2-carboxamide

A mixture of2-[6-amino-2-[4-(hydroxymethyl)cyclohexyl]-1,3-benzothiazol-5-yl]propan-2-ol(50.0 mg, 156 umol, Intermediate BHD),6-(trifluoromethyl)pyrazine-2-carboxylic acid (53.9 mg, 280 umol,Intermediate BGR), CMPI (51.8 mg, 202 umol) and DIEA (40.3 mg, 312 umol)in DMF (0.5 mL) was stirred at 25° C. for 2 hours. On completion, thereaction mixture was filtered. The filtrate was purified by reversephase (0.1% FA) to give the title compound (34.0 mg, 44% yield) asyellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.59 (s, 1H), 9.64 (s, 1H),9.48 (s, 1H), 9.08 (s, 1H), 7.91 (s, 1H), 6.23 (s, 1H), 4.46 (t, J=5.2Hz, 1H), 3.28 (t, J=5.6 Hz, 2H), 3.05 (m, 1H), 2.23-2.14 (m, 2H), 1.89(dd, J=2.8, 13.2 Hz, 2H), 1.64 (s, 6H), 1.61-1.53 (m, 2H), 1.50-1.41 (m,1H), 1.17-1.06 (m, 2H).

Step2—N-[2-(4-formylcyclohexyl)-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]-6-(trifluoromethyl)pyrazine-2-carboxamide

To a solution ofN-[2-[4-(hydroxymethyl)cyclohexyl]-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]-6-(trifluoromethyl)pyrazine-2-carboxamide(40.0 mg, 80.8 umol) in DCM (0.5 mF) was added DMP (44.6 mg, 105 umol).The reaction mixture was stirred at 25° C. for 2 hours. On completion,the reaction mixture was quenched with sat. aq. Na₂S₂O₃ (1 mF), thenadded sat. aq. NaHCO₃ until the pH=7˜8. The reaction mixture was dilutedwith water (10 mF), and extracted with DCM (3×10 mF). The combinedorganic layer was washed with brine (2×10 mF), dried over Na₂SO₄,filtered and concentrated in vacuo to give the title compound (34.0 mg,85% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.60-12.56 (m,1H), 9.63 (d, J=1.6 Hz, 2H), 9.48 (s, 1H), 9.08 (s, 1H), 7.91 (s, 1H),6.22 (s, 1H), 3.10 (m, 1H), 2.42-2.36 (m, 1H), 2.26-2.19 (m, 2H), 2.08(dd, J=3.2, 13.6 Hz, 2H), 1.72-1.64 (m, 2H), 1.64 (s, 5H), 1.62-1.59 (m,1H), 1.41 (m, 2H).

N-[2-(4-formylcyclohexyl)-5-methoxy-1,3-benzothiazol-6-yl]pyridine-2-carboxamide(Intermediate BJV)

Step 1 Methyl4-[5-methoxy-6-(pyridine-2-carbonylamino)-1,3-benzothiazol-2-yl]cyclohexanecarboxylate

To a mixture of methyl4-(6-bromo-5-methoxy-1,3-benzothiazol-2-yl)cyclohexanecarboxylate (350mg, 910 umol, Intermediate BFN) and pyridine-2-carboxamide (122 mg, 1.00mmol, CAS #1452-77-3) in dioxane (6.0 mL) was added Pd₂(dba)₃ (83.4 mg,91.0 umol), Xantphos (105 mg, 182 umol) and Cs₂CO₃ (593 mg, 1.82 mmol).The reaction mixture was stirred at 80° C. for 24 hours. On completion,the reaction mixture was filtered and concentrated in vacuo. The residuewas purified by column chromatography to give the title compound (120mg, 30% yield) as light yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.63(s, 1H), 9.05 (s, 1H), 8.77 (d, J=4.4 Hz, 1H), 8.21 (d, J=7.6 Hz, 1H),8.15-8.08 (m, 1H), 7.74-7.68 (m, 2H), 4.04 (s, 3H), 3.62 (s, 3H),3.15-3.05 (m, 1H), 2.47-2.39 (m, 1H), 2.23-2.16 (m, 2H), 2.07-2.00 (m,2H), 1.71-1.48 (m, 4H).

Step2—N-[2-[4-(hydroxymethyl)cyclohexyl]-5-methoxy-1,3-benzothiazol-6-yl]pyridine-2-carboxamide

To a mixture of methyl4-[5-methoxy-6-(pyridine-2-carbonylamino)-1,3-benzothiazol-2-yl]cyclohexanecarboxylate(120 mg, 282 umol) in THF (5.0 mL) was added LAH (21.4 mg, 564 umol).The reaction mixture was stirred at −70° C. for 3 hours. On completion,the reaction mixture was added NaOH solution (15%, 0.1 mL) at 0° C. anddried over Na₂SO₄. Then the mixture was filtered and the filtrate wasconcentrated in vacuo to give the title compound (55.0 mg, 49% yield) aslight yellow solid. LC-MS (ESI⁺) m/z 398.2 (M+H)+.

Step3—N-[2-(4-formylcyclohexyl)-5-methoxy-1,3-benzothiazol-6-yl]pyridine-2-carboxamide

To a mixture ofN-[2-[4-(hydroxymethyl)cyclohexyl]-5-methoxy-1,3-benzothiazol-6-yl]pyridine-2-carboxamide(25.0 mg, 62.8 umol) in DCM (10 mL) was added DMP (32.0 mg, 75.4 umol).The reaction mixture was stirred at 25° C. for 0.5 hour. On completion,the mixture was concentrated in vacuo to give the title compound (24.0mg, 96% yield, TFA salt) as brown solid. LC-MS (ESI⁺) m/z 396.2 (M+H)⁺.

3-[4-(3,9-diazaspiro[5.5]undecan-3-yl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate BJW)

Step 1—Tert-butyl9-[3-methyl-2-oxo-1-(2-trimethylsilylethoxymethyl)benzimidazol-4-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate

To a solution of4-bromo-3-methyl-1-(2-trimethylsilylethoxymethyl)benzimidazol-2-one (5.0g, 13.9 mmol, Intermediate BED) and tert-butyl3,9-diazaspiro[5.5]undecane-3-carboxylate (3.74 g, 14.6 mmol, CAS#173405-78-2) in toluene (50 mL) was added RuPhos (1.31 g, 2.80 mmol),Pd₂(dba)₃ (1.28 g, 1.40 mmol), t-BuONa (3.36 g, 34.9 mmol), then thereaction mixture was stirred at 80° C. for 2 hours. On completion, thereaction mixture was filtered, and the filtrate was concentrated invacuo to give a residue. The residue was purified by reverse phase (0.1%FA condition) to give the title compound (4.4 g, 59% yield) as yellowoil. LC-MS (ESI⁺) m/z 531.5 (M+1)⁺.

Step 2—Tert-butyl9-(3-methyl-2-oxo-1H-benzimidazol-4-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

To a solution of tert-butyl9-[3-methyl-2-oxo-1-(2-trimethylsilylethoxymethyl)benzimidazol-4-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate(4.4 g, 8.29 mmol) in THF (40 mL) was added TBAF (10.8 g, 41.4 mmol),then the reaction mixture was stirred at 75° C. for 24 hours. Oncompletion, the reaction mixture was diluted with H₂O (20 mL), and thenextracted with EA (2×100 mL), washed with brine (2×200 mL), dried overNa₂SO₄, filtered and concentrated in vacuo to give a residue. Theresidue was purified by column chromatography (SiO₂, petroleumether/ethyl acetate=10/1 to 2/1, PE/EA=1/1) to give the title compound(2.3 g, 69% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 10.21 (s,1H), 7.00-6.96 (m, 1H), 6.94-6.85 (m, 2H), 3.76 (s, 3H), 3.47-3.40 (m,4H), 3.04-2.86 (m, 4H), 1.79-1.58 (m, 6H), 1.48 (s, 9H), 1.46-1.35 (m,2H); LC-MS (ESI⁺) m/z 401.2 (M+1)⁺.

Step 3—Tert-butyl9-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-4-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate

To a solution of tert-butyl9-(3-methyl-2-oxo-1H-benzimidazol-4-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate(2.2 g, 5.49 mmol) in THF (20 mL) was added t-BuOK (924 mg, 8.24 mmol)at 0° C., and the mixture was stirred at 0° C. for 0.5 hour. Then asolution of [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]trifluoromethanesulfonate (2.30 g, 6.04 mmol, Intermediate IQ) in THF(20 mL) was added dropwise to the mixture, and the reaction mixture wasstirred at 20° C. for 16 hours. On completion, the mixture was acidifiedwith HCOOH until the pH=3-5, then diluted with water (100 mL), andextracted with EA (2×100 mL). The organic layer was washed with brine(100 mL), and then concentrated in vacuo to give a residue. The residuewas purified by reverse phase (0.1% FA condition) to give the titlecompound (2.3 mg, 66% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃)δ 7.40-7.34 (m, 2H), 6.94-6.85 (m, 2H), 6.84-6.81 (m, 2H), 6.28 (d,J=7.6 Hz, 1H), 5.21 (dd, J=5.2, 12.8 Hz, 1H), 5.03-4.92 (m, 2H), 3.80(s, 3H), 3.76 (s, 3H), 3.50-3.38 (m, 4H), 3.04-2.97 (m, 1H), 2.97-2.88(m, 4H), 2.87-2.77 (m, 1H), 2.68-2.55 (m, 1H), 2.19-2.12 (m, 1H),1.81-1.72 (m, 2H), 1.70-1.61 (m, 4H), 1.48 (s, 9H), 1.46-1.37 (m, 2H);LC-MS (ESI⁺) m/z 632.5 (M+1)⁺.

Step4—3-[4-(3,9-diazaspiro[5.5]undecan-3-yl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl9-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-4-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (500 mg,791 umol) in TFA (2.4 mL) was added TfOH (850 mg, 5.66 mmol, 500 uL),and the reaction mixture was stirred at 65° C. for 12 hours. Oncompletion, the reaction mixture concentrated in vacuo to give aresidue. The residue was purified by reverse phase (0.1% FA condition)to give the title compound (250 mg, 69% yield, FA salt) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.95 (s, 1H), 9.39 (s, 1H),7.01-6.94 (m, 2H), 6.91-6.83 (m, 1H), 5.35 (dd, J=5.2, 12.8 Hz, 1H),3.62 (s, 3H), 3.07-2.97 (m, 4H), 2.95-2.81 (m, 5H), 2.72-2.57 (m, 2H),2.05-1.93 (m, 1H), 1.85-1.66 (m, 4H), 1.63-1.45 (m, 4H).

Tert-butyl 9-bromo-3-azaspiro[5.5]undecane-3-carboxylate (IntermediateBJX)

Step 1—Tert-butyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate

To a solution of tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate(1.50 g, 5.61 mmol, CAS #873924-08-4) in THF (7.5 mL) was added NaBH₄(212 mg, 5.61 mmol,) at −10° C. The reaction mixture was stirred at 25°C. for 12 hours. On completion, the reaction mixture was quenched withwater (5 mL) and diluted with water (30 mL) and extracted with EA (3×50mL). The combined organic layer was dried over Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (1.50 g, 99% yield) ascolorless oil. ¹H NMR (400 MHz, CDCl₃) δ 3.73-3.63 (m, 1H), 3.39-3.35(m, 4H), 1.79-1.73 (m, 2H), 1.70-1.64 (m, 2H), 1.48 (d, J=6.4 Hz, 2H),1.46 (s, 9H), 1.45-1.40 (m, 2H), 1.35-1.32 (m, 2H), 1.24-1.17 (m, 2H).

Step 2—Tert-butyl 9-bromo-3-azaspiro[5.5]undecane-3-carboxylate

To a mixture of tert-butyl9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate (1.30 g, 4.83 mmol) andCBr₄ (3.20 g, 9.65 mmol) in DCM (20 mL) was added PPh₃ (2.66 g, 10.1mmol) at −10° C. The reaction mixture was stirred at −10° C. for 4hours. On completion, the reaction mixture was concentrated in vacuo.The residue was purified by silica gel chromatography to give the titlecompound (560 mg, 34% yield) as white solid. ¹H NMR (400 MHz, CDCl₃) δ4.22 (s, 1H), 3.41-3.33 (m, 4H), 2.11-2.01 (m, 2H), 1.99-1.88 (m, 2H),1.76-1.68 (m, 2H), 1.53-1.47 (m, 2H), 1.46 (s, 9H), 1.36-1.32 (m, 2H),1.32-1.25 (m, 2H).

3-[4-(3-Azaspiro[5.5]undecan-9-yl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate BJY)

Step 1—Tert-butyl9-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-3-azaspiro[5.5]undecane-3-carboxylate

To a 40 mL vial equipped with a stir bar was added3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (210mg, 621 umol, Intermediate HP), tert-butyl9-bromo-3-azaspiro[5.5]undecane -3-carboxylate (268 mg, 807 umol,Intermediate BJX), Ir[dF(CF₃)ppy]₂(dtbpy)(PF₆) (6.97 mg, 6.21 umol),NiCl₂.dtbbpy (1.24 mg, 3.11 umol), TTMSS (154 mg, 621 umol), and2,6-dimethylpyridine (133 mg, 1.24 mmol) in DME (8 mL). The vial wassealed and placed under nitrogen. The reaction was stirred andirradiated with a 34 W blue LED lamp (7 cm away), with cooling fan tokeep the reaction temperature at 25° C. for 16 hours. On completion, thereaction mixture was filtered and concentrated in vacuo. The residue waspurified by reverse phase (0.1% FA condition) to give the title compound(25.0 mg, 7% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.09(s, 1H), 7.07-6.93 (m, 3H), 5.40-5.33 (m, 1H), 3.57 (s, 3H), 3.31-3.27(m, 4H), 3.24-3.16 (m, 1H), 2.94-2.83 (m, 1H), 2.72-2.59 (m, 2H),2.03-1.94 (m, 1H), 1.79 (brd, J=12.5 Hz, 2H), 1.73-1.60 (m, 4H),1.59-1.52 (m, 2H), 1.40 (s, 9H), 1.34-1.25 (m, 4H).

Step2—3-[4-(3-Azaspiro[5.5]undecan-9-yl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a mixture of tert-butyl9-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-3-azaspiro[5.5]undecane-3-carboxylate (25.0 mg, 48.9 umol) in DCM (3 mL) was addedTFA (3 mL). The reaction mixture was stirred at 25° C. for 1 hour. Oncompletion, the reaction mixture was concentrated in vacuo to give thetitle compound (25 mg, 97% yield, TFA salt) as red oil. LCMS (ESI+) m/z411.3 (M+H)⁺.

3-(4-amino-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione(Intermediate BAP)

Step 1—2-(Methylamino)-3-nitro-benzoic acid

To a solution of MeNH₂/EtOH (54.0 mmol, 200 mL, 30% solution) was added2-fluoro-3-nitro-benzoic acid (10.0 g, 54.0 mmol) in portions at 0° C.Then the reaction mixture was stirred at 20° C. for 2 hrs. Oncompletion, the mixture was concentrated in vacuo. The residue wasdiluted with water (100 mL), acidified with citric acid to pH=3-5,stirred and filtered. The filter cake was dried in vacuo to give thetitle compound (9.60 g, 91% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 13.41 (s, 1H), 8.62 (s, 1H), 8.04 (dd, J=1.6, 8.0 Hz, 1H),7.97 (dd, J=1.6, 8.0 Hz, 1H), 6.72 (t, J=8.0 Hz, 1H), 2.70 (s, 3H).

Step 2—3-Methyl-4-nitro-1H-benzimidazol-2-one

To a solution of 2-(methylamino)-3-nitro-benzoic acid (8.60 g, 43.8mmol) and DIPEA (17.0 g, 132 mmol) in t-BuOH (200 mL) was added DPPA(12.1 g, 43.8 mmol) dropwise at 0° C. Then the reaction mixture wasstirred at 85° C. for 12 hours. On completion, the mixture was dilutedwith MeOH (100 mL), cooled to 10-20° C., filtered and the filter cakewas dried in vacuo to give the title compound (6.80 g, 80% yield) as ayellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.61 (s, 1H), 7.58 (dd,J=0.8, 8.0 Hz, 1H), 7.30 (dd, J=0.8, 8.0 Hz, 1H), 7.18-7.07 (m, 1H),3.34 (s, 3H).

Step3—1-[(4-Methoxyphenyl)methyl]-3-(3-methyl-4-nitro-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione

To a solution of 3-methyl-4-nitro-1H-benzimidazol-2-one (7.20 g, 37.3mmol) in THE (70 mL) was added t-BuOK (8.37 g, 74.6 mmol) at −10-0° C.One hour later, a solution of[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]trifluoromethanesulfonate (21.3 g, 55.9 mmol, Intermediate IQ) in THE(50 mL) was added into the above mixture and the reaction mixture wasstirred at 0-20° C. for 12 hrs. On completion, the mixture was acidifiedwith PA to pH=3-5, diluted with water (300 mL), and extracted with EA(2×300 mL). The organic layer was washed with brine (200 mL), thenconcentrated in vacuo. The residue was purified by reverse phase (0.1%PA condition) to give the title compound (5.80 g, 37% yield) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.69 (dd, J=0.8, 8.0 Hz, 1H), 7.46(d, J=8.0 Hz, 1H), 7.27-7.17 (m, 3H), 6.93-6.78 (m, 2H), 5.67 (dd,J=5.2, 12.8 Hz, 1H), 4.94-4.62 (m, 2H), 3.72 (s, 3H), 3.41 (s, 3H),3.11-2.98 (m, 1H), 2.89-2.70 (m, 2H), 2.17-2.08 (m, 1H).

Step 4—3-(3-Methyl-4-nitro-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione

To a solution of1-[(4-methoxyphenyl)methyl]-3-(3-methyl-4-nitro-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (2.00 g, 4.71 mmol) in TFA (20 mL) was added TfOH(2 mL). The reaction mixture was stirred at 60° C. for 12 hours. Oncompletion, the mixture was concentrated in vacuo. The residue waspurified by reverse phase (0.1% FA condition) to give the title compound(900 mg, 63% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.19(s, 1H), 7.68 (dd, J=0.8, 8.0 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.23 (t,J=8.0 Hz, 1H), 5.51 (dd, J=5.2, 12.8 Hz, 1H), 3.41 (s, 3H), 2.95-2.85(m, 1H), 2.80-2.60 (m, 2H), 2.13-2.06 (m, 1H).

Step 5—3-(4-Amino-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione

To a solution of3-(3-methyl-4-nitro-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (850mg, 2.79 mmol) in THF (50 mL) was added Pd/C (200 mg, 10% wt). Thereaction mixture was stirred at 20° C. for 12 hrs under H₂ (15 Psi)atmosphere. On completion, the mixture was filtered and the filtrate wasconcentrated in vacuo to give the title compound (0.70 g, 91% yield) asa pink solid. LC-MS (ESI⁺) m/z 275.1 (M+H)⁺.

3-(4-(2-Azaspiro[3.3]heptan-6-ylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(Intermediate BJZ)

Step 1—Tert-butyl6-((I-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate

To a solution of3-(4-amino-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (500mg, 1.82 mmol, Intermediate BAP) and tert-butyl6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (385 mg, 1.82 mmol, CAS#1181816-12-5) in the dioxane (10 mL) and DMF (5.0 mL) was addedTi(i-PrO)₄ (5.18 g, 18.2 mmol). The mixture was stirred at 80° C. for 15hours. Then the mixture was cooled down to 25° C. and NaBH₃CN (172 mg,2.73 mmol) was added. The mixture was stirred at 25° C. for 1 hour. Oncompletion, the reaction mixture was quenched by saturated NH₄Cl (aq,100 mL) and extracted with EA (3×100 mL). The organic layer was driedover Na₂SO₄, filtered and concentrated in vacuo and the residue waspurified by reversed phase (FA, 0.1%) to give the title compound (400mg, 48% yield) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.06 (s,1H), 6.85 (t, J=8.0 Hz, 1H), 6.53 (d, J=8.2 Hz, 1H), 6.30 (d, J=8.2 Hz,1H), 5.28 (dd, J=5.4, 12.8 Hz, 1H), 5.22 (d, J=6.8 Hz, 1H), 3.92 (s,2H), 3.80 (s, 2H), 3.60 (s, 3H), 2.93-2.82 (m, 1H), 2.73-2.65 (m, 1H),2.63-2.58 (m, 2H), 2.13-2.06 (m, 2H), 2.01-1.93 (m, 1H), 1.37 (s, 9H),0.88-0.85 (m, 2H).

Step2—3-(4-(2-Azaspiro[3.3]heptan-6-ylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

A solution of tert-butyl6-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]amino]-2-azaspiro[3.3]heptane-2-carboxylate(50 mg, 106 umol) in the DCM (1.0 mL) and TFA (0.5 mL) was stirred at25° C. for 1 hour. On completion, the reaction mixture was concentratedin vacuo to give the title compound (50 mg, 97% yield, TFA salt) asyellow solid. LC-MS (ESI⁺) m/z 370.3 (M+H)⁺.

3-(3-Methyl-2-oxo-4-piperazin-1-yl-benzimidazol-1-yl)piperidine-2,6-dione(Intermediate BKA)

Step 1—Tert-butyl4-[3-methyl-2-oxo-1-(2-trimethylsilylethoxymethyl)benzimidazol-4-yl]piperazine-1-carboxylate

To a solution of4-bromo-3-methyl-1-(2-trimethylsilylethoxymethyl)benzimidazol-2-one(2.50 g, 7.00 mmol, Intermediate BED) and tert-butylpiperazine-1-carboxylate (1.95 g, 10.5 mmol, CAS #143238-38-4) indioxane (50 mL) was added RuPhos (326 mg, 699 umol), t-BuONa (1.34 g,13.9 mmol) and Pd₂(dba)₃ (640 mg, 699 umol). The mixture was stirred at90° C. for 5 hours under N₂. On completion, the mixture was filteredthrough celite and concentrated in vacuo. The residue was purified byflash silica gel chromatography (PE:EA=3:1) to give the title compound(5.00 g, 77% yield) as yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 7.03-6.98(m, 2H), 6.95-6.91 (m, 1H), 5.22 (s, 2H), 3.62 (s, 3H), 3.57-3.51 (m,2H), 3.30 (br s, 2H), 3.16-2.92 (m, 4H), 2.79-2.61 (m, 2H), 1.43 (s,9H), 0.88-0.79 (m, 2H), −0.07 (s, 9H).

Step 2—Tert-butyl4-(3-methyl-2-oxo-1H-benzimidazol-4-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-[3-methyl-2-oxo-1-(2-trimethylsilylethoxymethyl)benzimidazol-4-yl]piperazine-1-carboxylate (5.00 g, 10.8 mmol) in THF (50 mL) was addedTBAF (26.1 g, 100 mmol). The mixture was stirred at 80° C. for 6 hours.On completion, the reaction mixture was concentrated in vacuo. Theresidue was diluted with water (50 mL), and extracted with EA (3×100mL). The combined organic layers were washed with brine (100 mL), driedover Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound (2.30 g, 64% yield) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆)δ 10.90 (s, 1H), 7.01-6.94 (m, 1H), 6.92-6.86 (m, 1H), 6.81 (d, J=7.6Hz, 1H), 3.27-3.17 (m, 4H), 3.15-2.99 (m, 3H), 1.68-1.57 (m, 4H), 1.48(s, 9H), 1.43-1.31 (m, 5H).

Step 3—Tert-butyl4-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-4-yl]piperazine-1-carboxylate

To a solution of tert-butyl4-(3-methyl-2-oxo-1H-benzimidazol-4-yl)piperazine-1-carboxylate (1.00 g,3.01 mmol) in THF (10 mL) was added t-BuOK (506 mg, 4.51 mmol). Themixture was stirred at 0° C. for 0.5 hour. Then,[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]trifluoromethanesulfonate (1.72 g, 4.51 mmol, Intermediate IQ) wasadded. The mixture was stirred at 0-25° C. for 3.5 hours. On completion,the reaction mixture was quenched with sat. aq. NH₄Cl (20 mL) at 0° C.,and extracted with EA (3×20 mL). The combined organic layers were washedwith brine (50 mL), dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified by reversed phase flash (0.1% FAcondition) to give the title compound (800 mg, 47% yield) as yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.21 (d, J=8.8 Hz, 2H), 6.96-6.91 (m,2H), 6.89-6.84 (m, 2H), 6.83-6.78 (m, 1H), 5.51 (dd, J=5.6, 12.8 Hz,1H), 4.79 (q, J=14.4 Hz, 2H), 4.05-3.86 (m, 2H), 3.73 (s, 3H), 3.63 (s,3H), 3.16-2.97 (m, 4H), 2.92-2.60 (m, 5H), 2.11-1.99 (m, 1H), 1.43 (s,9H).

Step4—3-(3-Methyl-2-oxo-4-piperazin-1-yl-benzimidazol-1-yl)piperidine-2,6-dione

To a solution of tert-butyl4-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-4-yl]piperazine-1-carboxylate (800 mg, 1.42 mmol) in TFA(8 mL) was added TfOH (1.70 g, 11.3 mmol). The mixture was stirred at60° C. for 4 hours. The mixture was concentrated in vacuo. The residuewas purified by reversed phase flash (0.1% FA condition) to give thetitle compound (300 mg, 61% yield) as yellow oil. LC-MS (ESI⁺) m/z 344.1(M+H)⁺.

1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazole-4-carbaldehyde(Intermediate WW)

To a solution of3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(500 mg, 1.48 mmol, Intermediate HP) in DMF (20 mL) was added TEA (448mg, 4.44 mmol), Pd(dppf)Cl₂ (162 mg, 221 umol) and Et₃SiH (515 mg, 4.44mmol). The reaction mixture was stirred at 80° C. for 16 hours under CO(50 Psi). On completion, the reaction mixture was concentrated in vacuoand purified by reverse phase (0.1% FA) to give the title compound (400mg, 47% yield) as a white solid. LC-MS (ESI⁺) m/z 288.0 (M+H)⁺.

3-[4-(2,7-Diazaspiro[3.5]nonan-2-ylmethyl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate BKB)

Step 1—Tert-butyl2-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]methyl]-2,7-diazaspiro[3.5]nonane-7-carboxylate

To a mixture of1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazole-4-carbaldehyde(600 mg, 2.09 mmol, Intermediate WW) in THF (8 mL) was added KOAc (615mg, 6.27 mmol). The mixture was stirred at −10° C. for 0.5 hour.Tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (567 mg, 2.51 mmol,CAS #896464-16-7) and NaBH(OAc)₃ (531 mg, 2.51 mmol) was added into themixture. The reaction mixture was stirred at 25° C. for 0.5 hour. Oncompletion, the reaction was quenched by water (5 mL) and CH₃CN (10 mL),then the mixture was concentrated in vacuo to give the residue. Theresidue was purified by reversed-phase HPLC (0.1% FA condition) to givethe title compound (460 mg, 44% yield) as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ 11.10 (s, 1H), 8.19 (s, 1H), 7.05 (dd, J=1.6, 6.8 Hz,1H), 6.93 (s, 1H), 5.37 (dd, J=5.2, 12.4 Hz, 1H), 3.80 (s, 2H), 3.65 (s,3H), 3.22 (br s, 5H), 2.99-2.91 (m, 4H), 2.76-2.62 (m, 2H), 2.07-1.93(m, 1H), 1.63-1.55 (m, 4H), 1.37 (s, 9H).

Step2—3-[4-(2,7-Diazaspiro[3.5]nonan-2-ylmethyl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a mixture of tert-butyl2-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]methyl]-2,7-diazaspiro[3.5]nonane-7-carboxylate(70.0 mg, 141 umol) in DCM (5 mL) was added TFA (48.1 mg, 422 umol). Thereaction mixture was stirred at 20° C. for 0.5 hour. On completion, themixture was concentrated in vacuo to give the title compound (71.0 mg,98% yield, TFA salt) as brown oil. LC-MS (ESI⁺) m/z 398.3 (M+H)⁺.

3-[3-Methyl-4-[methyl-[[7-(methylamino)spiro[3.5]nonan-2-yl]methyl]amino]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate BKC)

Step 1: Tert-butylN-methyl-N-[2-[[[3-methyl-2-oxo-1-(2-trimethylsilylethoxymethyl)benzimidazol-4-yl]amino]methyl]spiro[3.5]nonan-7-yl]carbamate

To a solution of tert-butylN-[2-(aminomethyl)spiro[3.5]nonan-7-yl]-N-methyl-carbamate (900 mg, 3.19mmol, Intermediate BCQ) and4-bromo-3-methyl-1-(2-trimethylsilylethoxymethyl)benzimidazol-2-one(1.37 g, 3.82 mmol, Intermediate BED) in dioxane (15 mL) was addedt-BuONa (612 mg, 6.37 mmol) and BrettPhos Pd G3 (288 mg, 318 umol) at25° C. The mixture was stirred at 80° C. for 16 hours. On completion,the reaction mixture was filtered and the filtrate was concentrated invacuo. The residue was purified by column chromatography (SiO₂,petroleum ether/ethyl acetate=20:1 to 8:1) to give the title compound(860 mg, 48% yield) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 6.98 (t,J=8.0 Hz, 1H), 6.68 (d, J=IF Hz, 1H), 6.48 (d, J=8.4 Hz, 1H), 5.28 (s,2H), 3.72 (s, 3H), 3.63-3.57 (m, 2H), 3.16 (d, J=7.6 Hz, 2H), 2.71 (s,3H), 2.60-2.50 (m, 1H), 2.10-2.05 (m, 1H), 1.95-1.87 (m, 2H), 1.66-1.61(m, 1H), 1.59-1.48 (m, 5H), 1.47 (s, 9H), 1.46-1.37 (m, 4H), 0.95-0.89(m, 2H), −0.03 (s, 9H); LC-MS (ESI⁺) m/z 559.4 (M+H)⁺.

Step 2: Tert-butylN-methyl-N-[2-[[methyl-[3-methyl-2-oxo-1-(2-trimethylsilylethoxymethyl)benzimidazol-4-yl]amino]methyl]spiro[3.5]nonan-7-yl]carbamate

To a solution of tert-butylN-methyl-N-[2-[[[3-methyl-2-oxo-1-(2-trimethylsilylethoxymethyl)benzimidazol-4-yl]amino]methyl]spiro[3.5]nonan-7-yl]carbamate (270 mg,483 umol) in HFIP (2 mL) was added methyl trifluoromethanesulfonate(87.2 mg, 531 umol) at 0° C. The reaction mixture was stirred at 0-25°C. for 7 hours. On completion, the reaction mixture was quenched withsat. aq NaHCO₃ (3 mL), diluted with H₂O (30 mL), extracted with EA (3×10mL). The combined organic layers were washed with brine (2×10 mL), driedover by Na₂SO₄, filtered and the filtrate was concentrated in vacuo. Theresidue was purified by reverse phase (0.1% FA condition) to give thetitle compound (250 mg, 81% yield) as colorless oil. LC-MS (ESL) m/z573.5 (M+H)⁺.

Step 3—Tert-butylN-methyl-N-[2-[[methyl-(3-methyl-2-oxo-1H-benzimidazol-4-yl)amino]methyl]spiro[3.5]nonan-7-yl]carbamate

To a solution of tert-butylN-methyl-N-[2-[[methyl-[3-methyl-2-oxo-1-(2-trimethylsilylethoxymethyl)benzimidazol-4-yl]amino]methyl]spiro[3.5]nonan-7-yl]carbamate (250 mg,392 umol) in THF (3 mL) was added TBAF (1.57 g, 6 mmol) at 25° C. Themixture was stirred at 80° C. for 12 hours. On completion, the reactionmixture was diluted with H₂O (15 mL), and extracted with EA (3×5 mL).The combined organic layers were washed with brine 10 mL (2×5 mL), driedover by Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound (170 mg, 97% yield) as a brown solid. LC-MS (ESI+) m/z 443.4(M+H)⁺.

Step 4—Tert-butylN-[2-[[[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-4-yl]-methyl-amino]methyl]spiro[3.5]nonan-7-yl]-N-methyl-carbamate

To a solution of tert-butylN-methyl-N-[2-[[methyl-(3-methyl-2-oxo-1H-benzimidazol-4-yl)amino]methyl]spiro[3.5]nonan-7-yl]carbamate (170 mg, 384 umol) in THF (2.5 mL)was added t-BuOK (86.2 mg, 768 umol) at 0° C. The mixture was stirred at0-10° C. for 0.5 hour. Then[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]trifluoromethanesulfonate (292 mg, 768 umol, Intermediate IQ) was addedto above mixture at 0° C. The reaction mixture was stirred at 0-25° C.for 2.5 hours. On completion, the reaction mixture was quenched byaddition of sat. aq. NH₄Cl (2 mL) and concentrated in vacuo. Then themixture was diluted with H₂O (15 mL) and extracted with EA (3×5 mL). Thecombined organic layers were washed with brine (2×5 mL), dried over byNa2SO4, filtered and the filtrate was concentrated in vacuo. The residuewas purified by reverse phase (0.1% FA condition) to give the titlecompound (200 mg, 77% yield) as a blue solid. ¹H NMR (400 MHz, DMSO-d6)δ 7.21 (d, J=8.8 Hz, 2H), 6.95-6.89 (m, 2H), 6.88-6.83 (m, 2H), 6.76 (s,1H), 5.50 (dd, J=5.6, 13.2 Hz, 1H), 4.89-4.70 (m, 2H), 3.72 (s, 3H),3.59 (s, 3H), 3.11-2.92 (m, 3H), 2.87-2.63 (m, 3H), 2.61 (s, 3H), 2.60(s, 3H), 2.42-2.34 (m, 1H), 2.07-2.00 (m, 1H), 1.92 (t, J=8.4 Hz, 1H),1.81-1.68 (m, 2H), 1.57 (d, J=10.0 Hz, 1H), 1.44-1.38 (m, 3H), 1.37 (s,9H), 1.34-1.19 (m, 5H); LC-MS (ESI+) m/z 674.3 (M+H)⁺.

Step5—3-[3-Methyl-4-[methyl-[[7-(methylamino)spiro[3.5]nonan-2-yl]methyl]amino]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[2-[[[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-4-yl]-methyl-amino]methyl]spiro[3.5]nonan-7-yl]-N-methyl-carbamate(200 mg, 296 umol) in TFA (3.2 mL) was added TfOH (4.53 mmol, 0.4 mL) at25° C. The mixture was stirred at 65° C. for 3 hours. On completion, thereaction mixture was concentrated in vacuo. The residue was purified byreverse phase (0.1% FA condition) to give the title compound (120 mg,89% yield) as a white solid. FC-MS (ESI+) m/z 454.4 (M+H)⁺.

3-[4-(2-Azaspiro[3.3]heptan-6-ylmethylamino)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate BKD)

Step 1—Tert-butyl6-(methoxymethylene)-2-azaspiro[3.3]heptane-2-carboxylate

To a suspension of chloro-(methoxymethyl)-triphenyl-phosphane (6.33 g,18.4 mmol, CAS #1181816-12-5) in toluene (45 mF) was added t-BuOK (2 g,18.4 mmol) at 0° C. The mixture was stirred at 10° C. for 0.5 hour. Tothe mixture was added a solution of tert-butyl 6-oxo-2-azaspiro [3.3]heptane-2-carboxylate (3.00 g, 14.2 mmol, CAS #4009-98-7) in toluene (35mF) at 10° C. The mixture was then stirred at 70° C. for 4 hours. Thereaction was then quenched with sat. aq. NH₄Cl (10 mF). The residue wasdiluted with water (20 mF), and extracted with EA (3×50 mF). Thecombined organic layer was washed with brine (20 mL), dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by columnchromatography on silica gel (PE:EA=50:1-15:1) to give the titlecompound as light yellow oil (1.20 g, 35% yield) ¹H NMR (400 MHz, CDCl₃)δ 5.81 (J=2.4 Hz, 1H), 3.92 (s, 4H), 3.56 (s, 3H), 2.87 (d, J=2.4 Hz,2H), 2.79 (d, J=1.6 Hz, 2H), 1.44 (s, 9H).

Step 2—Tert-butyl 6-formyl-2-azaspiro[3.3]heptane-2-carboxylate

To a solution of tert-butyl 6-(methoxymethylene)-2-azaspiro[3.3]heptane-2-carboxylate (400 mg, 1.67 mmol) in DCM (4 mL) and H₂O (2mL) was added TFA (1.0 mL) at 25° C. The mixture was stirred at 25° C.for 2 hours. On completion, the reaction was quenched with sat. aq.NaHCO₃ (10 mL). The mixture was concentrated in vacuo, and diluted withwater (10 mL), then extracted with EA (3×45 mL). The combined organiclayer was washed with brine (15 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by columnchromatography on silica gel (PE:EA=50: 1-15:1) to give the titlecompound (137 mg, 36% yield) as light yellow solid. ¹H NMR (400 MHz,CDCl₃) δ 9.73 (d, J=1.6 Hz, 1H), 3.95 (s, 2H), 3.84 (s, 2H), 3.16-3.04(m, 1H), 2.46-2.33 (m, 4H), 1.43 (s, 9H).

Step 3 Tert-butyl6-[[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]amino]methyl]-2-azaspiro[3.3]heptane-2-carboxylate

To a solution of tert-butyl6-formyl-2-azaspiro[3.3]heptane-2-carboxylate (80.0 mg, 355 umol),3-(4-amino-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (97.4mg, 355 umol, Intermediate BAP) in dioxane (4.5 mL) was added Ti(OEt)₄(162 mg, 710.22 umol) at 25° C. for 16 hours. Then to the mixture wasadded NaBH₃CN (44.6 mg, 710 umol) and the mixture was stirred at 25° C.for 1 hour. On completion, the reaction was quenched with water (20 mL),and extracted with EA (3×60 mL). The combined organic layer was driedover Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound (137 mg, 79% yield) as light yellow solid ¹H NMR (400 MHz,CDCl₃) δ 8.16 (s, 1H), 6.98-6.91 (m, 1H), 6.45 (d, J=8.0 Hz, 1H), 6.32(d, J=7.6 Hz, 1H), 5.20-5.11 (m, 1H), 3.96 (s, 2H), 3.85 (s, 2H), 3.73(s, 3H), 3.57 (d, J=6.4 Hz, 1H), 3.13 (d, J=7.2 Hz, 2H), 2.96 (s, 1H),2.89 (s, 1H), 2.40-2.33 (m, 3H), 2.29-2.24 (m, 1H), 2.24-2.16 (m, 2H),2.05 (s, 4H), 1.98-1.91 (m, 3H), 1.44 (s, 9H), 0.08 (s, 1H); LC-MS(ESI⁺) m/z 384.2 (M+H)⁺.

Step4—3-[4-(2-Azaspiro[3.3]heptan-6-ylmethylamino)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl6-[[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]amino]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (70.0 mg, 145 umol) in DCM(1.5 mL) was added TFA (1.5 mL) at 25° C. The mixture was stirred at 25°C. for 1 hour. On completion, the mixture was concentrated in vacuo togive the title compound as white solid (70.0 mg, 97% yield, TFA salt).¹H NMR (400 MHz, DMSO-d₆) δ 11.06 (s, 1H), 8.58 (d, J=2.4 Hz, 2H), 6.86(t, J=8.0 Hz, 1H), 6.52 (d, J=7.6 Hz, 2H), 6.42 (d, J=8.2 Hz, 2H), 5.28(dd, J=5.6, 12.4 Hz, 1H), 3.98 (t, J=6.0 Hz, 2H), 3.89 (t, J=6.0 Hz,2H), 3.60 (s, 3H), 3.04 (d, J=7.2 Hz, 2H), 2.93-2.81 (m, 1H), 2.70-2.56(m, 2H), 2.50 (d, J=1.6, 3.5 Hz, 11H), 2.46-2.39 (m, 1H), 2.36-2.28 (m,2H), 2.04-1.90 (m, 3H), 1.53 (s, 1H).

N-[2-(4-formyl-1-piperidyl)-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol6-yl]pyridine-carboxamide (Intermediate BKE)

Step 1—Methyl2-[4-(hydroxymethyl)-1-piperidyl]-6-(pyridine-2-carbonylamino)-1,3-benzothiazole-5-carboxylate

To a solution of methyl6-bromo-2-[4-(hydroxymethyl)-1-piperidyl]-1,3-benzothiazole-5-carboxylate(200 mg, 519 umol, Intermediate BCJ) and pyridine-2-carboxamide (76.1mg, 623 umol, CAS #1452-77-3) in dioxane (8 mL) was added Cs₂CO₃ (338mg, 1.04 mmol) and Pd₂(dba)₃ (47.5 mg, 51.9 umol) and Xantphos (60.1 mg,104 umol). The mixture was stirred at 80° C. for 24 hrs under N₂. Oncompletion, the mixture was filtered through celite and concentrated invacuo, the residue was purified by flash silica gel chromatography(PE:EA=0:1) to give the title compound (140 mg, 63% yield) as yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.82 (s, 1H), 9.23 (s, 1H),8.83-8.77 (m, 1H), 8.23-8.18 (m, 1H), 8.10-8.09 (m, 1H), 8.03 (s, 1H),7.70-7.53 (m, 1H), 4.56 (t, J=5.6 Hz, 1H), 4.09-4.03 (m, 2H), 3.95 (s,3H), 3.31-3.28 (m, 2H), 3.18 (dt, J=2.4, 12.6 Hz, 2H), 1.80 (d, J=13.2Hz, 2H), 1.73-1.63 (m, 1H), 1.30-1.19 (m, 2H).

Step2—N-[5-(1-hydroxy-1-methyl-ethyl)-2-[4-(hydroxymethyl)-1-piperidyl]-1,3-benzothiazol-6-yl]pyridine-2-carboxamide

To a solution of methyl2-[4-(hydroxymethyl)-1-piperidyl]-6-(pyridine-2-carbonylamino)-1,3-benzothiazole-5-carboxylate(140 mg, 328 umol,) in THF (10 mL) was added MeMgBr (3 M, 765 uL). Themixture was stirred at 0° C. for 4 hrs. On completion, the reactionmixture was quenched by addition 10 mL NH₄Cl at 0° C., and then dilutedwith 100 mL water and extracted with EA (3×100 mL). The combined organiclayers were washed with brine 100 mL, dried over Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (130 mg, 93% yield) asyellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.32 (s, 1H), 8.75 (s, 1H),8.70 (d, J=4.6 Hz, 1H), 8.22-8.16 (m, 1H), 8.09-8.01 (m, 1H), 7.66-7.63(m, 1H), 7.40 (s, 1H), 6.02 (s, 1H), 4.53 (t, J=5.4 Hz, 1H), 4.06-3.99(m, 2H), 3.29 (t, J=5.6 Hz, 3H), 3.13 (dt, J=2.4, 12.8 Hz, 2H),1.80-1.74 (m, 2H), 1.58 (s, 6H), 1.26-1.20 (m, 2H).

N-[2-(4-formyl-1-piperidyl)-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol6-yl]pyridine-carboxamide

To a solution ofN-[5-(1-hydroxy-1-methyl-ethyl)-2-[4-(hydroxymethyl)-1-piperidyl]-1,3-benzothiazol-6-yl]pyridine-2-carboxamide(130 mg, 304 umol) in DCM (5 mL) was added DMP (155 mg, 365 umol, 113uL). The mixture was stirred at 25° C. for 2 hrs. On completion, themixture was added 20 mL sat. NaHCO₃ aq. and 20 mL sat. Na₂S₂O₃ aq., thenextracted with DCM (3×20 mL). The combined organic layers were washedwith 50 mL brine, dried over Na₂SO₄; the mixture was concentrated invacuo to give the title compound (70.0 mg, 54% yield) as yellow solid.LC-MS (ESI⁺) m/z 425.2 (M+H)⁺.

Example 1 (Method 2). Synthesis ofN-[2-[4-[[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-1-piperidyl]methyl]-1-piperidyl]-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]-2-methyl-oxazole-4-carboxamide(I-4)

To a solution of3-[3-methyl-2-oxo-4-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione(87.8 mg, 256 umol, Intermediate AZK) in THE (1 mL) and DMP (0.5 mL) wasadded TEA until the pH=7˜8, then AcOH was added until the pH=6˜7. ThenN-[2-(4-formyl-1-piperidyl)-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]-2-methyl-oxazole-4-carboxamide(100 mg, 233 umol, Intermediate BFP) was added at 0° C. After thereaction mixture was stirred at 0° C. for 0.5 hr, NaBH(OAc)₃ (98.9 mg,466 umol) was added. The reaction mixture was stirred at 0° C. for 2hrs. On completion, the reaction mixture was filtered and concentratedin vacuo. The residue was purified by Prep-HPLC (column: PhenomenexSynergi C18 150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B %:9%-39%,10 min) to give the title compound (100 mg, 53% yield, FA) aswhite solid. LCMS (ESI+) m/z 755.3 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ11.49 (s, 1H), 11.09 (s, 1H), 8.62 (s, 1H), 8.60 (s, 1H), 7.38 (s, 1H),7.04-6.95 (m, 3H), 6.08 (s, 1H), 5.37 (dd, J=5.6, 12.4 Hz, 1H), 4.01 (d,J=11.6 Hz, 2H), 3.58 (s, 3H), 3.18-3.15 (m, 2H), 3.02-2.99 (m, 2H),2.94-2.84 (m, 1H), 2.77-2.68 (m, 1H), 2.65-2.59 (m, 1H), 2.51-2.51 (m,3H), 2.23 (m, 2H), 2.13-2.05 (m, 2H), 2.02-1.97 (m, 1H), 1.92-1.72 (m,8H), 1.57 (s, 6H), 1.25-1.15 (m, 2H).

TABLE 3 Compounds synthesized via Method 2 with the reductive aminationof various amines and aldehydes. Inter- Inter- LCMS mediate mediate(ES+) m/z I-# Amine Aldehyde (M + H)⁺ 1HNMR (400 MHz, DMSO-d6) δ I-5 AZKBAX 818.4 12.55 (s, 1H), 11.09 (s, 1H), 9.07 (s, 1H), 8.47-8.45 (m, 1H),8.38 (t, J = 8.4 Hz, 1H), 8.19 (d, J = 7.6 Hz, 1H), 7.89 (s, 1H),7.04-7.00 (m, 2H), 6.98-6.96 (m, 1H), 6.08-6.06 (m, 1H), 5.39-5.35 (m,1H), 3.59 (s, 3H), 3.25-3.19 (m, 2H), 3.09-3.02 (m, 1H), 2.99 (d, J =11.2 Hz, 2H), 2.93-2.84 (m, 1H), 2.77-2.61 (m, 2H), 2.20 (d, J = 7.2 Hz,4H), 2.08-1.94 (m, 6H), 1.78-1.75 (m, 3H), 1.63 (s, 6H), 1.59-1.56 (m,2H), 1.11-1.08 (m, 2H) I-6 AQK BAX 847.5 12.52 (br s, 1H), 9.08 (s, 1H),8.47-8.45 (m, 1H), 8.38 (t, J = 7.6 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H),7.89 (s, 1H), 6.99-6.83 (m, 3H), 6.07 (br s, 1H), 5.37-5.31 (m, 1H),3.64 (s, 3H), 3.30 (s, 4H), 3.15 (d, J = 11.2 Hz, 2H), 3.08- 3.03 (m,1H), 2.93-2.83 (m, 1H), 2.74-2.69 (m, 2H), 2.67-2.66 (m, 1H), 2.63-2.58(m, 1H), 2.44-2.41 (m, 1H), 2.28 (d, J = 6.8 Hz, 2H), 2.24 (s, 3H), 2.18(d, J = 11.2 Hz, 2H), 2.03-1.93 (m, 3H), 1.79 (d, J = 11.2 Hz, 2H), 1.63(s, 6H), 1.58-1.52 (m, 2H), 1.09-1.06 (m, 2H) I-7 AQK BHH 848.0 12.37(s, 1H), 11.08 (s, 1H), 8.78 (s, 1H), 8.45-8.43 (m, 1H), 8.37 (t, J =7.6 Hz, 1H), 8.17 (dd, J = 7.6, 0.8 Hz, 1H), 7.42 (s, 1H), 6.99-6.85 (m,3H), 5.95 (s, 1H), 5.34 (dd, J = 12.4, 5.6 Hz, 1H), 4.03 (d, J = 12.4Hz, 2H), 3.63 (s, 3H), 3.15 (d, J = 12.8 Hz, 4H), 2.90-2.84 (m, 1H),2.75-2.71 (m, 2H), 2.64-2.56 (m, 2H), 2.42-2.40 (m, 1H), 2.31 (d, J =8.0 Hz, 2H), 2.26 (s, 3H), 2.00- 1.96 (m, 1H), 1.85 (d, J = 12.4 Hz,2H), 1.80-1.78 (m, 3H), 1.69-1.62 (m, 2H), 1.58 (s, 6H), 1.21-1.18 (m,2H) I-8 APY BAX 846.3 12.55 (s, 1H), 11.09 (s, 1H), 9.07 (s, 1H),8.49-8.44 (m, 1H), 8.38 (t, J = 8.0 Hz, 1H), 8.19 (d, J = 7.6 Hz, 1H),7.89 (s, 1H), 6.95 (d, J = 4.8 Hz, 2H), 6.88-6.84 (m, 1H), 6.07 (s, 1H),5.36 (dd, J = 5.2, 12.4 Hz, 1H), 3.56 (s, 3H), 3.08-3.01 (m, 1H),2.94-2.83 (m, 5H), 2.69- 2.59 (m, 2H), 2.20-2.11 (m, 4H), 2.03-1.96 (m,1H), 1.94-1.83 (m, 4H), 1.74 (d, J = 10.0 Hz, 2H), 1.63 (s, 6H),1.61-1.48 (m, 5H), 1.40-1.31 (m, 1H), 1.30-1.16 (m, 2H), 1.12-0.98 (m,2H) I-9 AZF BAX 856.5 12.52 (s, 1H), 11.04 (s, 1H), 9.06 (s, 1H),8.49-8.43 (m, 1H), 8.41-8.31 (m, 1H), 8.18 (d, J = 7.6 Hz, 1H), 7.88 (s,1H), 7.10 (d, J = 8.0 Hz, 1H), 7.08-7.03 (m, 1H), 7.03-6.94 (m, 1H),6.11 (s, 1H), 5.36 (dd, J = 5.2, 12.4 Hz, 1H), 3.64 (s, 3H), 3.09-2.97(m, 1H), 2.94-2.80 (m, 3H), 2.75-2.58 (m, 2H), 2.45 (d, J = 6.4 Hz, 2H),2.21-2.08 (m, 4H), 2.06-1.97 (m, 1H), 1.94-1.81 (m, 4H), 1.94-1.82 (m,2H), 1.63 (s, 6H), 1.61-1.46 (m, 4H), 1.41-1.25 (m, 2H), 1.13-0.95 (m,2H) I-10 AZK BHG 819.4 12.64 (s, 1H), 11.09 (s, 1H), 9.52 (s, 1H), 9.32(s, 1H), 9.07 (s, 1H), 7.91 (s, 1H), 7.06-6.94 (m, 3H), 6.50- 6.21 (m,1H), 5.37 (dd, J = 5.2, 12.8 Hz, 1H), 3.59 (s, 3H), 3.15-3.03 (m, 2H),3.02-2.95 (m, 2H), 2.93-2.83 (m, 1H), 2.73-2.58 (m, 2H), 2.23-2.15 (m,4H), 2.10- 2.02 (m, 2H), 2.02-1.93 (m, 3H), 1.83-1.73 (m, 4H), 1.64 (s,6H), 1.63-1.54 (m, 3H), 1.18-1.02 (m, 2H) I-11 AZK BHH 819.4 12.37 (s,1H), 8.78 (s, 1H), 8.47-8.41 (m, 1H), 8.37 (t, J = 7.8 Hz, 1H),8.19-8.14 (m, 1H), 7.42 (s, 1H), 7.05- 6.94 (m, 3H), 6.21-5.70 (m, 1H),5.42-5.31 (m, 1H), 4.07-3.98 (m, 2H), 3.58 (s, 3H), 3.26-3.20 (m, 1H),3.20-3.13 (m, 2H), 2.98 (d, J = 10.8 Hz, 2H), 2.92- 2.82 (m, 1H),2.75-2.67 (m, 1H), 2.66-2.59 (m, 1H), 2.22 (d, J = 6.4 Hz, 2H),2.11-2.03 (m, 2H), 2.02-1.95 (m, 1H), 1.86 (d, J = 9.8 Hz, 3H),1.82-1.73 (m, 4H), 1.58 (s, 6H), 1.26-1.15 (m, 2H) I-12 AQK BJF 779.412.52 (s, 1H), 11.09 (s, 1H), 9.05 (s, 1H), 8.72 (d, J = 4.8 Hz, 1H),8.21 (d, J = 8.0 Hz, 1H), 8.12-8.05 (m, 1H), 7.87 (s, 1H), 7.67 (dd, J =4.4, 7.2 Hz, 1H), 7.01- 6.84 (m, 3H), 6.18-6.12 (m, 1H), 5.39-5.31 (m,1H), 3.64 (s, 3H), 3.15 (d, J = 10.0 Hz, 2H), 3.10-3.01 (m, 1H),2.94-2.84 (m, 1H), 2.78-2.68 (m, 3H), 2.65-2.55 (m, 3H), 2.30 (d, J =6.4 Hz, 2H), 2.26 (s, 3H), 2.18 (d, J = 11.6 Hz, 2H), 2.02-1.91 (m, 3H),1.84-1.77 (m, 2H), 1.71-1.66 (m, 1H), 1.63 (s, 6H), 1.61-1.51 (m, 3H),1.13-1.05 (m, 2H) I-13 BJG BHH 888.4 12.37 (s, 1H), 11.08 (s, 1H), 8.78(s, 1H), 8.47-8.40 (m, 1H), 8.36 (t, J = 8.0 Hz, 1H), 8.17-8.14 (m, 1H),7.42 (s, 1H), 7.00-6.92 (m, 2H), 6.90-6.82 (m, 1H), 5.94 (s, 1H), 5.34(dd, J = 5.2, 12.8 Hz, 1H), 4.01 (d, J = 12.8 Hz, 2H), 3.63 (s, 3H),3.15 (t, J = 12.0 Hz, 2H), 2.91- 2.82 (m, 5H), 2.71-2.59 (m, 2H),2.43-2.34 (m, 4H), 2.21 (d, J = 6.8 Hz, 2H), 2.03-1.95 (m, 1H),1.89-1.78 (m, 3H), 1.77-1.61 (m, 4H), 1.58 (s, 6H), 1.55-1.38 (m, 4H),1.25-1.11 (m, 2H) I-14 BJH BAX 802.4 12.54 (s, 1H), 11.12 (s, 1H), 9.07(s, 1H), 8.49-8.43 (m, 1H), 8.38 (t, J = 8.0 Hz, 1H), 8.18 (dd, J = 0.8,8.0 Hz, 1H), 7.89 (s, 1H), 7.15 (dd, J = 7.6, 11.2 Hz, 2H), 7.07- 6.98(m, 1H), 6.07 (s, 1H), 5.40 (dd, J = 5.2, 12.4 Hz, 1H), 3.67 (s, 3H),3.67-3.46 (m, 2H), 3.12-3.02 (m, 1H), 2.95-2.84 (m, 1H), 2.79-2.52 (m,3H), 2.45-2.23 (m, 4H), 2.18 (d, J = 11.2 Hz, 2H), 2.07-1.99 (m, 1H),1.93 (d, J = 11.20 Hz, 2H), 1.69-1.64 (m, 1H), 1.63 (s, 6H), 1.62-1.54(m, 2H), 1.18-1.02 (m, 2H) I-15 BJI BAX 915.4 12.54 (s, 1H), 11.05 (s,1H), 9.06 (s, 1H), 8.49-8.44 (m, 1H), 8.38 (t, J = 7.6 Hz, 1H), 8.20 (s,1H), 7.88 (s, 1H), 6.85 (t, J = 8.4 Hz, 1H), 6.49 (d, J = 8.0 Hz, 1H),6.41 (d, J = 8.4 Hz, 1H), 6.07 (s, 1H), 5.28 (dd, J = 5.2, 12.8 Hz, 1H),4.89 (s, 1H), 3.60 (s, 3H), 3.08-3.00 (m, 3H), 2.92-2.83 (m, 1H),2.73-2.64 (m, 1H), 2.60-2.52 (m, 2H), 2.28-2.20 (m, 3H), 2.18 (s, 3H),2.14 (s, 2H), 1.98- 1.87 (m, 4H), 1.83-1.75 (m, 2H), 1.63 (s, 6H), 1.59-1.42 (m, 8H), 1.34-1.13 (m, 5H), 1.09-0.97 (m, 2H) I-16 BIL BAX 859.512.55 (s, 1H), 11.14-11.00 (m, 1H), 9.07 (s, 1H), 8.50- 8.44 (m, 1H),8.38 (t, J = 7.6 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.89 (s, 1H), 6.94(t, J = 8.0 Hz, 1H), 6.72 (d, J = 7.6 Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H),6.07 (s, 1H), 5.32 (dd, J = 5.2, 12.8 Hz, 1H), 3.57 (s, 4H), 3.57 (s,3H), 3.09-3.02 (m, 1H), 2.94-2.82 (m, 1H), 2.73-2.66 (m, 1H), 2.64-2.57(m, 1H), 2.37 (d, J = 6.4 Hz, 1H), 2.32-2.27 (m, 2H), 2.20-2.10 (m, 4H),2.02-1.89 (m, 3H), 1.78 (s, 4H), 1.63 (s, 6H), 1.62-1.53 (m, 4H), 1.13-1.00 (m, 2H) I-17 AQK BJJ 848.2 12.74 (s, 1H), 11.09 (s, 1H), 9.38 (d, J= 5.2 Hz, 1H), 9.08 (s, 1H), 8.44 (d, J = 5.2 Hz, 1H), 7.91 (s, 1H),7.00- 6.94 (m, 1H), 6.93-6.89 (m, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.22(s, 1H), 5.35 (dd, J = 5.6, 12.4 Hz, 1H), 3.64 (s, 3H), 3.15 (d, J =11.6 Hz, 2H), 3.10-3.04 (m, 1H), 2.93-2.85 (m, 1H), 2.76-2.66 (m, 3H),2.64-2.58 (m, 1H), 2.47-2.42 (m, 1H), 2.29 (m, 2H), 2.25 (s, 3H), 2.18(m, 2H), 2.02-1.91 (m, 3H), 1.80 (m, 2H), 1.71-1.65 (m, 2H), 1.64 (s,6H), 1.61-1.48 (m, 3H), 1.14-1.01 (m, 2H) I-19 AZK BJO 724.5 11.06 (s,1H), 10.39 (s, 1H), 9.43 (d, J = 1.2 Hz, 1H), 9.16 (d, J = 5.2 Hz, 1H),8.72 (s, 1H), 8.17 (dd, J = 1.2, 5.2 Hz, 1H), 7.29 (s, 1H), 7.06-6.91(m, 3H), 5.40- 5.30 (m, 1H), 4.06-3.99 (m, 2H), 3.97 (s, 3H), 3.58 (s,3H), 3.24-3.11 (m, 3H), 3.03-2.94 (m, 2H), 2.93-2.79 (m, 1H), 2.77-2.67(m, 1H), 2.65-2.56 (m, 1H), 2.25- 2.18 (m, 2H), 2.13-2.03 (m, 2H),2.02-1.94 (m, 1H), 1.91-1.83 (m, 3H), 1.82-1.71 (m, 4H), 1.25-1.11 (m,2H) I-20 AZK BJQ 734.5^(b) 12.49 (s, 1H), 11.08 (s, 1H), 9.37 (d, J =1.6 Hz, 1H), 9.13 (d, J = 5.2 Hz, 1H), 8.77 (s, 1H), 8.17 (dd, J = 1.2,5.2 Hz, 1H), 7.41 (s, 1H), 7.05-6.92 (m, 3H), 6.18 (s, 1H), 5.36 (dd, J= 5.2, 12.4 Hz, 1H), 4.08-3.95 (m, 2H), 3.58 (s, 3H), 3.25-3.20 (m, 1H),3.16 (t, J = 11.6 Hz, 2H), 3.02 (d, J = 10.0 Hz, 2H), 2.92-2.82 (m, 1H),2.73- 2.56 (m, 2H), 2.28 (d, J = 5.6 Hz, 2H), 2.20-2.07 (m, 2H),2.03-1.95 (m, 1H), 1.91-1.72 (m, 7H), 1.58 (s, 6H), 1.29-1.11 (m, 2H)I-21 BJR BHH 860.5 12.36 (s, 1H), 11.1 (s, 1H), 8.77 (s, 1H), 8.46-8.41(m, 1H), 8.38-8.34 (m, 1H), 8.17-8.15 (m, 1H), 7.41 (s, 1H), 7.00-6.92(m, 1H), 6.90-6.83 (m, 2H), 6.01-5.87 (m, 1H), 5.37-5.30 (m, 1H), 4.00(d, J = 12.4 Hz, 2H), 3.62 (s, 3H), 3.17-3.08 (m, 2H), 3.07-2.77 (m,8H), 2.72-2.57 (m, 4H), 2.36-2.30 (m, 2H), 2.04-1.94 (m, 1H), 1.88 (s,2H), 1.80 (d, J = 10.4 Hz, 4H), 1.58 (s, 6H), 1.26-1.13 (m, 2H) I-22 AQKBJS 780.4 12.54 (s, 1H), 11.09 (s, 1H), 9.37 (d, J = 1.6 Hz, 1H),9.09-9.02 (m, 1H), 8.94 (d, J = 2.4 Hz, 1H), 8.81 (dd, J = 1.6, 2.4 Hz,1H), 7.92-7.86 (m, 1H), 7.01-6.93 (m, 1H), 6.92-6.80 (m, 2H), 6.32-6.23(m, 1H), 5.35 (dd, J = 6.0, 12.5 Hz, 1H), 3.64 (s, 3H), 3.15 (d, J =12.0 Hz, 2H), 3.08-3.01 (m, 1H), 2.95-2.83 (m, 1H), 2.75-2.69 (m, 2H),2.65-2.58 (m, 1H), 2.47-2.40 (m, 2H), 2.29 (d, J = 6.8 Hz, 2H),2.26-2.22 (m, 3H), 2.18 (d, J = 10.8 Hz, 2H), 2.02-1.92 (m, 3H),1.83-1.76 (m, 2H), 1.73- 1.66 (m, 2H), 1.63 (s, 6H), 1.61 (s, 1H), 1.58(s, 1H), 1.55 (s, 1H), 1.13-1.01 (m, 2H) I-23 AQK BJT 794.6 12.60 (s,1H), 11.09 (s, 1H), 9.13 (s, 1H), 9.06 (s, 1H), 8.83 (s, 1H), 7.89 (s,1H), 7.01-6.94 (m, 1H), 6.92- 6.84 (m, 2H), 6.30-6.09 (m, 1H), 5.35 (dd,J = 5.2, 12.6 Hz, 1H), 3.64 (s, 3H), 3.15 (d, J = 11.2 Hz, 2H), 3.10-3.01 (m, 1H), 2.94-2.82 (m, 1H), 2.75-2.66 (m, 3H), 2.64 (s, 3H), 2.60(s, 1H), 2.47-2.42 (m, 1H), 2.29 (d, J = 6.8 Hz, 2H), 2.25 (s, 3H), 2.18(d, J = 10.4 Hz, 2H), 2.02-1.90 (m, 3H), 1.80 (d, J = 11.2 Hz, 2H), 1.69(s, 2H), 1.64 (s, 6H), 1.62-1.52 (m, 3H), 1.15-0.99 (m, 2H) I-24 BJR BFS832.4 12.36 (s, 1H), 11.08 (s, 1H), 8.79 (s, 1H), 8.46-8.41 (m, 1H),8.39-8.37 (m, 1H), 8.16 (d, J = 7.6 Hz, 1H), 7.46 (s, 1H), 6.99-6.93 (m,1H), 6.89-6.84 (m, 2H), 5.95 (s, 1H), 5.34 (dd, J = 5.6, 12.4 Hz, 1H),4.17 (t, J = 8.0 Hz, 2H), 3.78 (m, 2H), 3.61 (s, 3H), 3.10-3.06 (m, 2H),2.97 (m, 4H), 2.91-2.77 (m, 4H), 2.75-2.69 (m, 4H), 2.65- 2.55 (m, 6H),2.03-1.93 (m, 2H), 1.92-1.74 (m, 5H), 1.57 (s, 6H) I-25 AZF BJF 788.412.58-12.45 (m, 1H), 11.11 (s, 1H), 9.09-9.02 (m, 1H), 8.72 (d, J = 4.8Hz, 1H), 8.21 (d, J = 7.6 Hz, 1H), 8.11- 8.05 (m, 1H), 7.87 (s, 1H),7.70-7.63 (m, 1H), 7.12 (d, J = 7.6 Hz, 1H), 7.09-7.04 (m, 1H),7.03-6.97 (m, 1H), 6.16 (s, 1H), 5.38 (dd, J = 5.6, 13.2 Hz, 1H), 3.64(s, 3H), 3.10-3.01 (m, 2H), 2.94-2.84 (m, 1H), 2.77-2.68 (m, 1H),2.66-2.60 (m, 1H), 2.52 (s, 8H), 2.20-2.15 (m, 2H), 2.06-1.99 (m, 1H),1.91 (d, J = 10.8 Hz, 2H), 1.86-1.79 (m, 2H), 1.72-1.67 (m, 1H), 1.63(s, 6H), 1.62-1.54 (m, 2H), 1.50-1.38 (m, 2H), 1.16-1.03 (m, 2H) I-26BJH BJS 735.4 12.54 (s, 1H), 11.13 (s, 1H), 9.39-9.35 (m, 1H), 9.09-9.00 (m, 1H), 8.94 (d, J = 2.4 Hz, 1H), 8.80 (dd, J = 1.2, 2.4 Hz, 1H),7.89 (s, 1H), 7.18-7.07 (m, 2H), 7.05- 6.94 (m, 1H), 6.29 (s, 1H), 5.40(dd, J = 5.2, 12.4 Hz, 1H), 3.70-3.64 (m, 3H), 3.64-3.57 (m, 2H),3.12-3.01 (m, 1H), 2.96-2.83 (m, 1H), 2.77-2.60 (m, 2H), 2.35- 2.26 (m,5H), 2.23-2.12 (m, 2H), 2.07-1.99 (m, 1H), 1.98-1.85 (m, 2H), 1.72-1.64(m, 1H), 1.63 (s, 6H), 1.61-1.54 (m, 2H), 1.18-1.01 (m, 2H) I-27 BJH BJF734.3 12.50 (s, 1H), 11.13 (s, 1H), 9.04 (s, 1H), 8.73 (d, J = 4.4 Hz,1H), 8.22 (d, J = 7.6 Hz, 1H), 8.10-8.06 (m, 1H), 7.88 (s, 1H), 7.68(dd, J = 4.8, 7.6 Hz, 1H), 7.20- 7.11 (m, 2H), 7.06-7.00 (m, 1H),6.18-6.14 (m, 1H), 5.41 (dd, J = 5.2, 12.6 Hz, 1H), 3.68 (s, 3H),3.67-3.58 (m, 2H), 3.13-3.02 (m, 1H), 2.96-2.85 (m, 1H), 2.78- 2.59 (m,4H), 2.38-2.28 (m, 5H), 2.18 (d, J = 11.2 Hz, 2H), 2.09-2.00 (m, 1H),1.98-1.89 (m, 2H), 1.64 (s, 6H), 1.62-1.55 (m, 2H), 1.17-1.04 (m, 2H)I-28 AZK BJJ 819.4 12.74 (s, 1H), 11.09 (s, 1H), 9.38 (d, J = 5.2 Hz,1H), 9.08 (s, 1H), 8.44 (d, J = 5.2 Hz, 1H), 7.91 (s, 1H), 7.05- 6.95(m, 3H), 6.22 (s, 1H), 5.37 (dd, J = 5.2, 12.4 Hz, 1H), 3.59 (s, 3H),3.22 (m, 1H), 3.09-3.04 (m, 1H), 2.99 (m, 2H), 2.87 (m, 1H), 2.75-2.64(m, 2H), 2.23-2.16 (m, 4H), 2.10-1.91 (m, 6H), 1.82-1.75 (m, 4H), 1.64(s, 6H), 1.63-1.56 (m, 3H), 1.15-1.04 (m, 2H) I-29 AZK BJU 819.2 12.58(s, 1H), 11.09 (s, 1H), 9.63 (s, 1H), 9.47 (s, 1H), 9.07 (s, 1H), 7.90(s, 1H), 7.07-6.93 (m, 3H), 6.22 (s, 1H), 5.37 (dd, J = 5.2, 12.4 Hz,1H), 3.59 (s, 3H), 3.22 (dd, J = 4.8, 10.0 Hz, 1H), 3.11-3.03 (m, 1H),2.99 (d, J = 10.4 Hz, 2H), 2.94-2.83 (m, 1H), 2.75-2.60 (m, 2H),2.24-2.14 (m, 4H), 2.10-1.93 (m, 5H), 1.85-1.73 (m, 4H), 1.64 (s, 6H),1.63-1.54 (m, 3H), 1.16-1.03 (m, 2H) I-30 BJR BJF 791.5 12.52 (s, 1H),11.08 (s, 1H), 9.05 (s, 1H), 8.72 (d, J = 4.0 Hz, 1H), 8.28 (s, 1H, FA),8.21 (d, J = 7.6 Hz, 1H), 8.08 (t, J = 8.0 Hz, 1H), 7.87 (s, 1H),7.72-7.61 (m, 1H), 7.01-6.92 (m, 1H), 6.91-6.81 (m, 2H), 6.24-6.05 (m,1H), 5.38-5.31 (m, 1H), 3.62 (s, 3H), 3.13-3.05 (m, 2H), 3.05-2.93 (m,5H), 2.91-2.83 (m, 1H), 2.75- 2.57 (m, 4H), 2.38-2.32 (m, 2H), 2.21-2.11(m, 2H), 2.03-1.95 (m, 1H), 1.94-1.85 (m, 4H), 1.85-1.75 (m, 2H), 1.63(s, 6H), 1.56 (d, J = 11.2 Hz, 2H), 1.43-1.32 (m, 1H), 1.16-1.02 (m, 2H)I-31 BJR BCN 831.3 11.08 (s, 1H), 10.50 (s, 1H), 9.00 (s, 1H), 8.50-8.45(m, 1H), 8.44-8.38 (m, 1H), 8.24 (d, J = 1.2 Hz, 1H), 7.71 (s, 1H),6.99-6.93 (m, 1H), 6.90-6.84 (m, 2H), 5.36- 5.31 (m, 1H), 4.02 (s, 3H),3.62 (s, 3H), 3.13-3.02 (m, 4H), 3.01-2.92 (m, 4H), 2.90-2.83 (m, 1H),2.70-2.61 (m, 3H), 2.35 (d, J = 6.4 Hz, 2H), 2.16 (d, J = 11.6 Hz, 2H),2.04-1.95 (m, 1H), 1.89 (d, J = 9.6 Hz, 4H), 1.81 (dd, J = 2.4, 5.2 Hz,2H), 1.63-1.50 (m, 2H), 1.44-1.32 (m, 1H), 1.16-1.03 (m, 2H) I-32 BILBHH 860.3 12.36 (s, 1H), 11.13-11.00 (m, 1H), 8.78 (s, 1H), 8.46- 8.41(m, 1H), 8.36 (d, J = 8.0 Hz, 1H), 8.16 (d, J = 7.6 Hz, 1H), 7.42 (s,1H), 6.98-6.91 (m, 1H), 6.72 (d, J = 8.0 Hz, 1H), 6.67 (d, J = 8.0 Hz,1H), 5.94 (s, 1H), 5.34- 5.29 (m, 1H), 4.09-3.94 (m, 2H), 3.58-3.56 (m,7H), 3.20-3.10 (m, 2H), 2.94-2.80 (m, 1H), 2.73-2.61 (m, 2H), 2.39-2.26(m, 4H), 2.19-2.12 (m, 2H), 2.03-1.93 (m, 1H), 1.90-1.73 (m, 7H), 1.58(s, 6H), 1.22-1.10 (m, 2H) I-33 AQK BJV 751.5 11.09 (s, 1H), 10.64 (s,1H), 9.06 (s, 1H), 8.80-8.76 (m, 1H), 8.23 (d, J = 7.6 Hz, 1H),8.14-8.10 (m, 1H), 7.77- 7.72 (m, 1H), 7.71 (s, 1H), 6.97 (d, J = 7.6Hz, 1H), 6.93-6.85 (m, 2H), 5.38-5.33 (m, 1H), 4.05 (s, 3H), 3.67-3.61(m, 3H), 3.16 (d, J = 10.8 Hz, 3H), 3.11- 3.02 (m, 1H), 2.96-2.84 (m,1H), 2.79-2.65 (m, 4H), 2.65-2.58 (m, 1H), 2.29 (d, J = 6.4 Hz, 2H),2.25 (s, 2H), 2.19 (d, J = 10.4 Hz, 2H), 2.05-1.89 (m, 3H), 1.86- 1.76(m, 2H), 1.73-1.50 (m, 5H), 1.15-1.01 (m, 2H) I-34 BJW BAX 887.5 12.55(s, 1H), 11.08 (s, 1H), 9.07 (s, 1H), 8.51-8.43 (m, 1H), 8.38 (t, J =8.0 Hz, 1H), 8.19 (dd, J = 0.8, 7.6 Hz, 1H), 7.89 (s, 1H), 7.02-6.92 (m,2H), 6.90-6.79 (m, 1H), 6.08 (s, 1H), 5.34 (dd, J = 5.2, 12.8 Hz, 1H),3.63 (s, 3H), 3.07-3.02 (m, 1H), 2.92-2.83 (m, 5H), 2.71- 2.59 (m, 2H),2.41-2.31 (m, 4H), 2.22-2.11 (m, 4H), 2.02-1.96 (m, 1H), 1.95-1.86 (m,2H), 1.79-1.65 (m, 3H), 1.63 (s, 6H), 1.62-1.31 (m, 8H), 1.13-0.99 (m,2H) I-35 BJY BAX 886.5 12.55 (s, 1H), 11.09 (s, 1H), 9.07 (s, 1H),8.49-8.45 (m, 1H), 8.38 (t, J = 8.0 Hz, 1H), 8.18 (s, 1H), 7.89 (s, 1H),7.07-7.03 (m, 1H), 7.00 (t, J = 8.0 Hz, 1H), 6.97-6.92 (m, 1H), 6.07 (s,1H), 5.40-5.32 (m, 1H), 3.57 (s, 3H), 3.20 (d, J = 2.4 Hz, 1H),3.07-3.02 (m, 1H), 2.91-2.84 (m, 1H), 2.76-2.69 (m, 1H), 2.65-2.58 (m,2H), 2.36 (s, 3H), 2.17 (d, J = 5.6 Hz, 4H), 2.02-1.97 (m, 1H),1.94-1.89 (m, 2H), 1.80-1.75 (m, 2H), 1.69-1.64 (m, 4H), 1.63 (s, 6H),1.62-1.52 (m, 5H), 1.41-1.36 (m, 2H), 1.31-1.24 (m, 2H), 1.06 (m, 2H)I-36 BJR BAX 859.6 12.55 (s, 1H), 11.08 (s, 1H), 9.07 (s, 1H), 8.49-8.43(m, 1H), 8.38 (t, J = 8.0 Hz, 1H), 8.23-8.17 (m, 2H), 7.89 (s, 1H),6.99-6.93 (m, 1H), 6.90-6.84 (m, 2H), 6.07 (d, J = 2.0 Hz, 1H),5.38-5.31 (m, 1H), 3.62 (s, 3H), 3.15-2.95 (m, 8H), 2.92-2.83 (m, 1H),2.70-2.57 (m, 3H), 2.37 (d, J = 6.4 Hz, 2H), 2.16 (d, J = 11.8 Hz, 2H),2.03-1.96 (m, 1H), 1.89 (d, J = 10.2 Hz, 4H), 1.85- 1.77 (m, 2H), 1.63(s, 6H), 1.59-1.50 (m, 2H), 1.44- 1.34 (m, 1H), 1.16-1.03 (m, 2H) I-37BJR BJV 763.5 11.09 (s, 1H), 10.63 (s, 1H), 9.04 (s, 1H), 8.77 (d, J =4.4 Hz, 1H), 8.20 (d, J = 5.6 Hz, 1H), 8.14-8.08 (m, 1H), 7.74-7.70 (m,1H), 7.69 (s, 1H), 7.00-6.85 (m, 3H), 5.39-5.31 (m, 1H), 4.04 (s, 3H),3.62 (s, 3H), 3.34 (s, 2H), 3.22 (s, 2H), 3.09-2.95 (m, 3H), 2.93-2.83(m, 1H), 2.72-2.62 (m, 3H), 2.61-2.54 (m, 2H), 2.17 (d, J = 11.6 Hz,2H), 2.06-1.73 (m, 8H), 1.62-1.50 (m, 2H), 1.50-1.40 (m, 1H), 1.19-1.04(m, 2H) I-38 BJZ BAX 845.6 12.55 (s, 1H), 11.06 (s, 1H), 9.07 (s,1H),8.49-8.45 (m, 1H), 8.39 (t, J = 7.8 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H),7.89 (s, 1H), 6.85 (t, J = 8.2 Hz, 1H), 6.53 (br d, J = 7.8 Hz, 1H),6.30 (d, J = 8.2 Hz, 1H), 6.08 (s, 1H), 5.29 (dd, J = 5.0, 12.6 Hz, 1H),5.21 (d, J = 6.8 Hz, 1H), 3.73- 3.67 (m, 1H), 3.61 (s, 3H), 3.28-3.13(m, 3H), 3.08- 2.99 (m, 1H), 2.92-2.83 (m, 1H), 2.74-2.65 (m, 1H),2.65-2.57 (m, 1H), 2.57-2.53 (m, 2H), 2.34 (d, J = 6.4 Hz, 2H), 2.16 (d,J = 11.0 Hz, 2H), 2.05 (dd, J = 8.4, 11.0 Hz, 2H), 2.00-1.94 (m, 1H),1.87 (d, J = 10.0 Hz, 2H), 1.64 (s, 6H), 1.61-1.51 (m, 2H), 1.13-1.02(m, 2H) I-39 BKA BAX 819.3 12.55 (s, 1H), 11.09 (s, 1H), 9.07 (s, 1H),8.51-8.44 (m, 1H), 8.39 (t, J = 7.6 Hz, 1H), 8.21-8.17 (m, 1H), 7.90 (s,1H), 7.03-6.93 (m, 2H), 6.89 (d, J = 7.6 Hz, 1H), 6.08 (s, 1H),5.40-5.31 (m, 1H), 3.63 (s, 3H), 3.12- 2.86 (m, 8H), 2.72-2.58 (m, 3H),2.28-2.15 (m, 6H), 2.05-1.91 (m, 4H), 1.64 (s, 6H), 1.62-1.55 (m, 2H),1.19-1.06 (m, 2H) I-40 BKB BAX 873.4 12.54 (s, 1H), 11.10 (s, 1H), 9.06(s, 1H), 8.50-8.43 (m, 1H), 8.38 (t, J = 8.0 Hz, 1H), 8.20-8.17 (m, 1H),7.88 (s, 1H), 7.06 (d, J = 6.8 Hz, 1H), 6.98-6.92 (m, 2H), 6.07 (s, 1H),5.39-5.35 (m, 1H), 3.91-3.74 (m, 2H), 3.68-3.63 (m, 3H), 3.12-2.95 (m,5H), 2.94-2.82 (m, 2H), 2.79-2.58 (m, 4H), 2.18-2.15 (m, 2H), 2.00-1.97(m, 1H), 1.93-1.84 (m, 2H), 1.78 (s, 4H), 1.63 (s, 6H), 1.61-1.53 (m,2H), 1.18-1.03 (m, 2H) I-41 BKC BAX 929.4 12.54 (s, 1H), 11.09 (s, 1H),9.06 (s, 1H), 8.50-8.43 (m, 1H), 8.38 (t, J = 7.6 Hz, 1H), 8.18 (d, J =8.4 Hz, 1H), 7.88 (s, 1H), 6.99-6.90 (m, 2H), 6.89-6.82 (m, 1H), 6.07(s, 1H), 5.34 (dd, J = 5.2, 12.8 Hz, 1H), 3.59 (s, 3H), 3.52 (s, 2H),3.04-2.92 (m, 4H), 2.71-2.63 (m, 2H), 2.60 (s, 3H), 2.42-2.36 (m, 1H),2.22 (d, J = 6.4 Hz, 2H), 2.17 (s, 3H), 2.14 (s, 1H), 2.03-1.97 (m, 1H),1.89 (d, J = 10.8 Hz, 3H), 1.81-1.68 (m, 3H), 1.63 (s, 6H), 1.58-1.49(m, 5H), 1.42-1.31 (m, 2H), 1.27-1.16 (m, 4H), 1.07-0.97 (m, 2H) I-42BKD BAX 859.6 δ 12.54 (s, 1H), 11.05 (s, 1H), 9.06 (s, 1H), 8.48-8.44(m, 1H), 8.38 (t, J = 7.6 Hz, 1H), 8.18 (d, J = 7.6 Hz, 1H), 7.88 (s,1H), 6.85 (t, J = 8.0 Hz, 1H), 6.50 (d, J = 8.0 Hz, 1H), 6.40 (d, J =8.4 Hz, 1H), 5.28 (dd, J = 5.6, 12.8 Hz, 1H), 4.93 (d, J = 3.6 Hz, 1H),3.60 (s, 3H), 3.29 (s, 2H), 3.21 (s, 2H), 3.07-2.98 (m, 3H), 2.93-2.82(m, 1H), 2.73-2.54 (m, 2H), 2.47-2.39 (m, 2H), 2.33 (d, J = 4.6 Hz, 2H),2.24-2.11 (m, 4H), 2.00-1.93 (m, 1H), 1.92-1.82 (m, 4H), 1.63 (s, 6H),1.54 (J = 10.4, 12.5 Hz, 2H), 1.40-1.31 (m, 1H), 1.12-1.00 (m, 2H) I-43BJR BKE 792.2 12.32 (s, 1H), 11.08 (s, 1H), 8.75 (s, 1H), 8.70 (d, J =4.4 Hz, 1H), 8.18 (d, J = 7.8 Hz, 1H), 8.06 (dt, J = 1.7, 7.7 Hz, 1H),7.64 (dt, J = 1.1, 6.2 Hz, 1H), 7.40 (s, 1H), 7.00-6.93 (m, 1H),6.90-6.84 (m, 2H), 6.07-5.98 (m, 1H), 5.34 (dd, J = 5.2, 12.6 Hz, 1H),4.04-3.96 (m, 2H), 3.62 (s, 3H), 3.17-3.07 (m, 4H), 3.03-2.93 (m, 4H),2.92-2.82 (m, 1H), 2.71-2.59 (m, 4H), 2.39-2.36 (m, 2H), 2.03-1.74 (m,8H), 1.58 (s, 6H), 1.27-1.14 (m, 2H) I-65 BBD BAX 873.2 12.55 (s, 1H),11.06 (s, 1H), 9.12-9.07 (m, 1H), 9.07- 8.96 (m, 1H), 8.50-8.44 (m, 1H),8.39 (t, J = 8.0 Hz, 1H), 8.19 (dd, J = 0.8, 7.6 Hz, 1H), 7.88 (s, 1H),6.85 (t, J = 8.0 Hz, 1H), 6.54 (d, J = 7.6 Hz, 1H), 6.31 (d, J = 8.0 Hz,1H), 6.11-6.04 (m, 1H), 5.29 (dd, J = 5.2, 12.8 Hz, 1H), 5.26-5.16 (m,1H), 3.93-3.77 (m, 1H), 3.62 (s, 3H), 3.50-3.34 (m, 2H), 3.14-3.04 (m,1H), 3.03- 2.76 (m, 4H), 2.71-2.56 (m, 3H), 2.31-2.24 (m, 1H), 2.23-2.14(m, 2H), 2.00-1.89 (m, 4H), 1.88-1.76 (m, 3H), 1.76-1.65 (m, 3H),1.63(s, 6H), 1.62-1.52 (m, 2H), 1.30-1.16 (m, 2H) ^(a)For Method 2, whenthe amine is the HCl salt, TEA was added to free base the salt, followedby HOAc to adjust the pH to 3-4 or 5-7. KOAc could also be used in placeof the TEA/HOAc combination. The reaction was run anywhere from 0.5-48hrs The reaction temperature was run anywhere from −25° C. to rt. Thefinal products were isolated under standard purification techniquesincluding reverse HPLC, silica gel chromatography, and prep-TLC withappropriate solvent conditions. ^(b)LCMS is (M-18)⁺ ion.

Example 2. Synthesis ofN-[2-[4-(hydroxymethyl)cyclohexyl]-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide(I-1)

To a solution of methyl2-[4-(hydroxymethyl)cyclohexyl]-6-[[6-(trifluoromethyl)pyridine-2-carbonyl]amino]-1,3-benzothiazole-5-carboxylate(120 mg, 243 umol, synthesized via Step 1 of Intermediate BAX) in THF(10 mL) was added MeMgBr (3 M, 405 uL) and the mixture was stirred at 0°C. for 2 hrs. On completion, the reaction mixture was quenched byaddition 10 mL sat. NH₄Cl at 0° C., and then diluted with 50 mL waterand extracted with EA (50 mL×3). The combined organic layers were washedwith 100 mL brine, dried over Na₂SO₄, filtered and concentrated in vacuoto give a residue. The residue was purified by pre-HPLC (column:Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225%FA)-ACN]; B %: 44%-74%, 10 min) to give the title compound (80.0 mg, 65%yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.56 (s, 1H), 9.07(s, 1H), 8.51-8.45 (m, 1H), 8.39 (t, J=8.0 Hz, 1H), 8.20 (d, J=7.6 Hz,1H), 7.94-7.88 (m, 1H), 6.08 (s, 1H), 4.46 (t, J=5.2 Hz, 1H), 3.28 (t,J=5.6 Hz, 2H), 3.10-3.00 (m, 1H), 2.19 (d, J=11.2 Hz, 2H), 1.94-1.84 (m,2H), 1.64 (s, 6H), 1.61-1.53 (m, 2H), 1.50-1.40 (m, 1H), 1.19-1.06 (m,2H); LC-MS (ESI⁺) m/z 494.0 (M+1)⁺.

Example 3. Synthesis ofN-(2-((1r,4r)-4-(hydroxymethyl)cyclohexyl)-5-methoxybenzo[d]thiazol-6-yl)-6-(trifluoromethyl)picolinamide (I-2)

To a solution of methyl4-[5-methoxy-6-[[6-(trifluoromethyl)pyridine-2-carbonyl]amino]-1,3-benzothiazol-2-yl]cyclohexanecarboxylate(50.0 mg, 101 umol, synthesized via Step 1 of Intermediate BCN) in theTHF (1 mL) was added LiAlH₄ (7.69 mg, 202 umol) under -40° C. Themixture was stirred at −40° C. for 1 hr. On completion, the reaction wasquenched by water (0.2 mL) and NaOH (15% aq, 0.2 mL). The mixture wasdried over Na2SO4, filtered and concentrated in vacuo. The residue waspurified by prep-TLC (PE:EA=1:3) to give the title compound (40.0 mg,85% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H),9.11 (s, 1H), 8.51 (d, J=7.6 Hz, 1H), 8.14 (t, J=7.6 Hz, 1H), 7.88 (dd,J=0.8, 7.6 Hz, 1H), 7.54 (s, 1H), 4.06 (s, 3H), 3.55 (d, J=4.0 Hz, 2H),3.10-3.00 (m, 1H), 2.36-2.27 (m, 2H), 2.01 (dd, J=3.0, 13.6 Hz, 2H),1.77-1.67 (m, 2H), 1.66-1.60 (m, 1H), 1.38-1.30 (m, 1H), 1.25-1.14 (m,2H); LC-MS (ESI+) m/z 466.0 (M+1)⁺.

Example 4. Synthesis of6-(1,1-difluoroethyl)-N-(2-((1r,4r)-4-(hydroxymethyl)cyclohexyl)-5-methoxybenzo[d]thiazol-6-yl)picolinamide(I-3)

To a solution of methyl4-[6-[[6-(1,1-difluoroethyl)pyridine-2-carbonyl]amino]-5-methoxy-1,3-benzothiazol-2-yl]cyclohexanecarboxylate(315 mg, 643 umol, synthesized via Step 1 of Intermediate BCV) in theTHF (5 mL) was added LiAlH₄ (36.6 mg, 965 umol) at −40° C. The mixturewas stirred at −40° C. for 1 hr. On completion, the reaction wasquenched by water (0.5 mL) and NaOH (15% aq, 0.5 mL). The mixture wasdried over Na₂SO₄, filtered and the filtrate was concentrated to give aresidue. The residue was purified by prep-TLC (PE:EA=1:3) to give thetitle compound (100 mg, 33% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 10.78 (s, 1H), 9.13 (s, 1H), 8.39 (d, J=7.6 Hz, 1H), 8.07 (t,J=7.6 Hz, 1H), 7.89 (dd, J=1.0, 7.6 Hz, 1H), 7.54 (s, 1H), 4.05 (s, 3H),3.55 (d, J=5.6 Hz, 2H), 3.10-3.00 (m, 1H), 2.32 (dd, J=3.2, 13.6 Hz,2H), 2.18 (t, J=18.8 Hz, 3H), 2.01 (dd, J=3.2, 13.2 Hz, 2H), 1.77-1.67(m, 2H), 1.66-1.60 (m, 1H), 1.35 (s, 1H), 1.25-1.15 (m, 2H); LC-MS(ESI⁺) m/z 462.1 (M+1)⁺.

Example 5. IRAK4 MSD Degradation in OCI-LY10

Degradation of IRAK4 in OCI-LY10 is quantitatively measured using MesoScale Discovery technology. OCI-LY10 cells are seeded in 96-well plates(Corning 3799) with a density of 300,000 cells per well in 100 μL freshmedia. Compounds are then added to the assay plates with a final topconcentration of 1 to 10 μM in a 1:3 dilution series with total of 8doses. The assay plates are then incubated for 4 to 24 hours at 37° C.under 5% CO₂. The assay plates are then centrifuged for 5 minutes andthe cell pellets are treated with 100 μL/well RIPA lysis buffer (BostonBioProducts BP-115D) with proteinase inhibitors. To prepare MSD assayplates (Meso Scale Discovery Catalog number L15XA-3), the plates arecoated with 2 μg/mL capture antibody (mouse Anti-IRAK4 antibody [2H9],ab 119942) in PBS, at 40 μL/well. The plates are then incubatedovernight at 4° C., washed 3 times with 150 μL/well TBST buffer (CellSignaling Technology, Catalog number 9997S) and blocked with 150 μL/wellblocking buffer (Meso Scale Discovery Catalog number R93BA-4). Celllysates are then added to MSD assay plates and the plates were incubatedat room temperature for 1 hour. The plates are then washed 3 times with150 μL/well TBST buffer and 25 μL/well primary detection antibody(rabbit Anti-IRAK4 antibody [Y279], from Abeam. Catalog number ab32511,1 μg/mL). The assay plates are then incubated at room temperature for 1hour, washed 3 times with 150 μL/well TBST buffer and 25 μL/wellsecondary detection antibody, SULFO-TAG anti-rabbit antibody are added(anti rabbit antibody from Meso Scale Discovery, Catalog number R32AB-1,1 μg/mL). The assay plates are then incubated at room temperature for 1hour, washed 3 times with 150 μL/well TBST buffer, and 150 μL/well MSDreading buffer (Meso Scale Discovery catalog number R92TC-2) is added.The plates are then analyzed by a MSD reader (Meso Scale Discovery,Model Quick Plex SQ 120). The data is then analyzed by software Prism7.0 from GraphPad and the dose-depended IRAK4 degradation are fit usinga three-parameter logistic equation to calculate DC₅₀.

IRAK4 MSD degradation results in OCI-LY10 cells for compounds of theinvention are presented in Table 4. The letter codes for IRAK4 DC₅₀include: A (<0.05 μM); B (0.05-0.1 μM); C (0.1-0.5 μM); D (0.5-1.0 μM);and E (>1.0 μM).

TABLE 4 IRAK4 MSD Degradation in OCI-LY10 Results Compound # IRAK4degradation in IRAK4 degradation in OCI-LY10 at 4 hrs: OCI-LY10 at 24hrs: DC₅₀ (μM) DC₅₀ (μM)

Example 6. Cell Viability Assay with OCI-LY10 and SUDHL-2

Compound-mediated viability effect on OCI-LY10 or SUDHL-2 isquantitatively determined using the CellTiter-Glo® Luminescent CellViability Assay kit from Promega (Catalog number G7570) followingmanufacturer's recommended procedures. Briefly, OCI-LY10 or SUDHL-2cells are seeded into 384 well plates (Grenier Bio-One, Catalog number781080) with a density of 10,000 cells per well. Compounds are thenadded to the assay plate with final top concentration of 10 μM and 1:3dilution series with total of 9 doses. The final DMSO concentration isnormalized to 0.2%. The assay plates are incubated at 37° C. for 4 daysunder 5% CO₂. Then the assay plate is equilibrated at room temperaturefor 10 minutes. To determine cell viability, 30 μL CellTiter Glo reagentis added to each well and the assay plate is centrifuged at 1000 rpm for30 second, incubated at room temperature for 10 min, and analyzed bydetecting the luminescence using a multimode plate reader (EnVision2105, PerkinElmer). The data is then analyzed by software Prism 7.0 fromGraphPad and the dose response curves are fit using a three-parameterlogistic equation to calculate IC₅₀.

CTG Cell Viability Assay—OCI-LY10 and SUDHL-2 results for compounds ofthe invention are presented in Table 5. The letter codes for IRAK4 IC₅₀include: A (<0.05 μM); B (0.05-0.1 μM); C (0.1-0.5 μM); D (0.5-1.0 μM);and E (>1.0 μM).

TABLE 5 CTG Cell Viability Assay Results Compound # CTG Cell CTG CellViability Viability Assay - Assay - OCI-LY10: SUDHL-2: IC₅₀ (μM) IC₅₀(μM)

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments that utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example.

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: IRAK is an IRAKbinding moiety capable of binding to IRAK4, said compound of formula Iis a compound of formulae I-a:

or a pharmaceutically acceptable salt thereof, wherein: each R^(x) isindependently hydrogen, deuterium, R^(z), halogen, —CN, —NO₂, —OR, —SR,—NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —CFR₂, —CF₂R, —CF₃, —CR₂(OR),—CR₂(NR₂), —C(O)R, —C(O)OR, —C(O)NR₂, —C(S)NR₂, —C(O)N(R)OR, —OC(O)R,—OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, —N(R)S(O)₂R,—N⁺(O⁻)R₂, —OP(O)R₂, —OP(O)(OR)₂, —OP(O)(OR)NR₂, —OP(O)(NR₂)₂, —P(O)R₂,—SiR₃, —Si(OR)R₂, or

 or two R^(x) groups are optionally taken together to form an optionallysubstituted 5-7 membered partially unsaturated or aryl fused ring having0-3 heteroatoms independently selected from nitrogen, oxygen, andsulfur; each R is independently hydrogen, or an optionally substitutedgroup selected from C₁₋₆ aliphatic, phenyl, a 3-7 membered saturated orpartially unsaturated heterocyclic having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, and a 5-6 memberedheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, or: two R groups on the same carbon ornitrogen are optionally taken together with their intervening atoms toform a 4-7 membered saturated, partially unsaturated, or heteroaryl ringhaving 0-3 heteroatoms, in addition to the carbon or nitrogen,independently selected from nitrogen, oxygen, and sulfur; each R^(y) isindependently hydrogen, deuterium, R^(z), halogen, —CN, —NO₂, —OR, —SR,—NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —CF₂R, —CF₃, —CR₂(OR), —CR₂(NR₂),—C(O)R, —C(O)OR, —C(O)NR₂, —C(S)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂,—N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, —N(R)S(O)₂R, —OP(O)R₂,—OP(O)(OR)₂, —OP(O)(OR)NR₂, —OP(O)(NR₂)₂, —SiR₃, —SF₅, or

each R^(z) is independently an optionally substituted group selectedfrom C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partiallyunsaturated heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, and a 5-6 memberedheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; Ring Q is selected from benzo or a fused5-6 membered heteroaryl ring having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur; Ring T is selected fromphenyl, a 4-11 membered saturated or partially unsaturated monocyclic,bicyclic, bridged bicyclic, or spirocyclic carbocyclic or heterocyclicring having 1-3 heteroatoms independently selected from nitrogen,oxygen, and sulfur, or a 5-10 membered monocyclic or bicyclic heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur, wherein Ring T is further optionally substitutedwith 1-2 oxo groups; L^(x) is a covalent bond or a C₁₋₃ bivalentstraight or branched saturated or unsaturated hydrocarbon chain wherein1-2 methylene units of the chain are independently and optionallyreplaced with -Cy^(x)-, —O—, —S—, —C(O)—, —C(S)—, —CR₂—, —CRF—, —CF₂—,—NR—, —N═CR—, —CR═CR—, or —S(O)₂—, wherein R of —CR₂—, —CRF—, —NR—,—N═CR—, or —CR═CR— can combine with R^(x) or R^(y) to form a 4-7membered saturated or partially unsaturated carbocyclic or heterocyclicring having 1-3 heteroatoms independently selected from nitrogen,oxygen, and sulfur; each -Cy^(x)- is independently an optionallysubstituted ring selected from a 3-5 membered saturated or partiallyunsaturated carbocyclic or heterocyclic ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, and a 5membered heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, wherein -Cy^(x)- is optionallysubstituted with 1-2 oxo groups; X is a covalent bond or an optionallysubstituted bivalent ring selected from phenylenyl, a 4-11 memberedsaturated or partially unsaturated monocyclic, bicyclic, bridgedbicyclic, or spirocyclic carbocyclylenyl or heterocyclylenyl having 1-3heteroatoms independently selected from nitrogen, oxygen, and sulfur,and a 5-6 membered heteroarylenyl having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur; x is 0, 1, 2, 3 or 4; y is0, 1, 2, 3 or 4; L is a covalent bond or a bivalent, saturated orunsaturated, straight or branched C₁₋₅₀ hydrocarbon chain, wherein 0-6methylene units of L are independently replaced by —C(D)(H)—, —C(D)₂-,-Cy-, —O—, —N(R)—, —Si(R)₂—, —Si(OH)(R)-, —Si(OH)₂—, —P(O)(OR)—,—P(O)(R)-, —P(O)(NR₂)—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)₂—,—N(R)S(O)₂—, —S(O)₂N(R)—, —N(R)C(O)—, —C(O)N(R)—, —OC(O)N(R)—,—N(R)C(O)O—,

each -Cy- is independently an optionally substituted bivalent ringselected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7membered saturated or partially unsaturated carbocyclylenyl, a 4-7membered saturated or partially unsaturated spiro carbocyclylenyl, an8-10 membered bicyclic saturated or partially unsaturatedcarbocyclylenyl, a 4-7 membered saturated or partially unsaturatedheterocyclylenyl having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, a 4-7 membered saturated or partiallyunsaturated spiro heterocyclylenyl having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclicsaturated or partially unsaturated heterocyclylenyl having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur, a5-6 membered heteroarylenyl having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, and an 8-10 memberedbicyclic heteroarylenyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur; r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or10; and DIM is a degradation inducing moiety.
 2. The compound of claim1, wherein said compound is a compound selected from any one of thefollowing formulae:

or a pharmaceutically acceptable salt thereof.
 3. The compound of claim1, wherein the DIM is an E3 ubiquitin ligase binding moiety (LBM),lysine mimetic, or hydrogen atom.
 4. The compound of claim 3, whereinLBM is a cereblon E3 ubiquitin ligase binding moiety of formula I-aa:

or a pharmaceutically acceptable salt thereof, wherein: X¹ is a bivalentmoiety selected from a covalent bond, —CH₂—, —CHCF₃—, —SO₂—, —S(O)—,—P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—, —C(S)—, and

X² is a carbon atom or silicon atom; X³ is a bivalent moiety selectedfrom —CR₂—, —NR—, —O—, —S—, and —Si(R₂)—; R¹ is hydrogen, deuterium,halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R, —N(R)₂, —P(O)(OR)₂,—P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R, —Si(OH)(R)₂, —Si(R)₃, or anoptionally substituted C₁₋₄ aliphatic; each R² is independentlyhydrogen, deuterium, —R⁶, halogen, —CN, —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃,—S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR,—C(R)₂N(R)C(O)R, —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂,—OP(O)(OR)₂, —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,—N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,—N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R; Ring A is a bi- ortricyclic ring selected from

Ring B is a fused ring selected from 6-membered aryl, 6-memberedheteroaryl containing 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, 5 to 7-membered saturated or partiallyunsaturated carbocyclyl, 5 to 7-membered saturated or partiallyunsaturated heterocyclyl with 1-3 heteroatoms independently selectedfrom boron, nitrogen, oxygen, silicon, and sulfur, and 5-memberedheteroaryl with 1-4 heteroatoms independently selected from nitrogen,oxygen and sulfur; R³ is selected from hydrogen, halogen, —OR, —N(R)₂,and —SR; each R⁴ is independently hydrogen, —R⁶, halogen, —CN, —NO₂,—OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,—C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,or —N(R)S(O)₂R; R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN; each R⁶ isindependently an optionally substituted group selected from C₁₋₆aliphatic, phenyl, a 4-7 membered saturated or partially unsaturatedheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur; L¹ is a covalent bond or a C₁₋₃ bivalent straight or branchedsaturated or unsaturated hydrocarbon chain wherein 1-2 methylene unitsof the chain are independently and optionally replaced with —O—, —C(O)—,—C(S)—, —C(R)₂—, —CH(R)—, —C(F)₂—, —N(R)—, —S—, —S(O)₂— or —(C)═CH—; mis 0, 1, 2, 3 or 4; each R is independently hydrogen, or an optionallysubstituted group selected from C₁₋₆ aliphatic, phenyl, a 4-7 memberedsaturated or partially unsaturated heterocyclic having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, and a 5-6membered heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogenare optionally taken together with their intervening atoms to form a 4-7membered saturated, partially unsaturated, or heteroaryl ring having 0-3heteroatoms, in addition to the nitrogen, independently selected fromnitrogen, oxygen, and sulfur.
 5. The compound of claim 4, wherein saidcompound is a compound selected from any one of the following formulae:

or a pharmaceutically acceptable salt thereof.
 6. The compound of claim3, wherein LBM is a cereblon E3 ubiquitin ligase binding moiety offormula I-dd:

or a pharmaceutically acceptable salt thereof, wherein: X¹ is a bivalentmoiety selected from a covalent bond, —CH₂—, —CHCF₃—, —SO₂—, —S(O)—,—P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—, —C(S)—, and

X² is a carbon atom or silicon atom; X³ is a bivalent moiety selectedfrom —CR₂—, —NR—, —O—, —S—, and —Si(R₂)—; R¹ is hydrogen, deuterium,halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R, —NR₂, —P(O)(OR)₂, —P(O)(NR₂)OR,—P(O)(NR₂)₂, —Si(OH)₂R, —Si(OH)(R)₂, —Si(R)₃, or an optionallysubstituted C₁₋₄ aliphatic; Ring C is a mono- or bicyclic ring selectedfrom

each of R² and R^(3a) is independently hydrogen, deuterium, —R⁶,halogen, —CN, —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂,—S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,—C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,—OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)N(R)₂,—N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂, —N(R)P(O)(OR)(NR₂),—N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R; Ring D is selected from a 6-memberedaryl, 6-membered heteroaryl containing 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, 5 to 7-membered saturated orpartially unsaturated carbocyclyl, 5 to 7-membered saturated orpartially unsaturated heterocyclyl with 1-3 heteroatoms independentlyselected from boron, nitrogen, oxygen, silicon, and sulfur, and5-membered heteroaryl with 1-4 heteroatoms independently selected fromnitrogen, oxygen and sulfur; each R⁴ is independently hydrogen, —R⁶,halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R,—C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,—N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R; R⁵ is hydrogen, C₁₋₄aliphatic, or —CN; each R⁶ is independently an optionally substitutedgroup selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated orpartially unsaturated heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, and a 5-6membered heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur; L¹ is a covalent bond or a C₁₋₃bivalent straight or branched saturated or unsaturated hydrocarbon chainwherein 1-2 methylene units of the chain are independently andoptionally replaced with —O—, —C(O)—, —C(S)—, —C(R)₂—, —CH(R)—, —C(F)₂—,—N(R)—, —S—, —S(O)₂— or —(C)═CH—; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3or 4; p is 0 or 1, wherein when p is 0, the bond connecting Ring C andRing D is connected to

 and each R is independently hydrogen, or an optionally substitutedgroup selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated orpartially unsaturated heterocyclic having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, and a 5-6 memberedheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen areoptionally taken together with their intervening atoms to form a 4-7membered saturated, partially unsaturated, or heteroaryl ring having 0-3heteroatoms, in addition to the nitrogen, independently selected fromnitrogen, oxygen, and sulfur.
 7. The compound of claim 6, wherein saidcompound is a compound of formula I-a-11:

or a pharmaceutically acceptable salt thereof.
 8. (canceled)
 9. Thecompound of claim 3, wherein LBM is a cereblon E3 ubiquitin ligasebinding moiety of formula I-hh:

or a pharmaceutically acceptable salt thereof, wherein: X¹ is a bivalentmoiety selected from a covalent bond, —CH₂—, —CHCF₃—, —SO₂—, —S(O)—,—P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—, —C(S)—, and

X² is a carbon atom, nitrogen atom, or silicon atom; X³ is a bivalentmoiety selected from —CR₂—, —NR—, —O—, —S—, and —Si(R₂)—; R¹ ishydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R, —N(R)₂,—P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R, —Si(OH)(R)₂, —Si(R)₃,or an optionally substituted C₁₋₄ aliphatic; each R is independentlyhydrogen, or an optionally substituted group selected from C₁₋₆aliphatic, phenyl, a 4-7 membered saturated or partially unsaturatedheterocyclic having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur, or: two R groups on the same nitrogen are taken together withtheir intervening atoms to form a 4-7 membered saturated, partiallyunsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition tothe nitrogen, independently selected from nitrogen, oxygen, and sulfur;each R² is independently hydrogen, deuterium, —R⁶, halogen, —CN, —NO₂,—OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —C(O)R,—C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R, —C(R)₂N(R)C(O)N(R)₂,—OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂, —OP(O)(OR)(NR₂),—OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R,—NP(O)R₂, —N(R)P(O)(OR)₂, —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or—N(R)S(O)₂R; each R⁶ is independently an optionally substituted groupselected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated orpartially unsaturated heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, and a 5-6membered heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur; each of Ring E, Ring F, and Ring G isindependently a fused ring selected from 6-membered aryl, 6-memberedheteroaryl containing 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, 5 to 7-membered saturated or partiallyunsaturated carbocyclyl, 5 to 7-membered saturated or partiallyunsaturated heterocyclyl with 1-3 heteroatoms independently selectedfrom boron, nitrogen, oxygen, silicon, and sulfur, and 5-memberedheteroaryl with 1-4 heteroatoms independently selected from nitrogen,oxygen and sulfur; L¹ is a covalent bond or a C₁₋₃ bivalent straight orbranched saturated or unsaturated hydrocarbon chain wherein 1-2methylene units of the chain are independently and optionally replacedwith —O—, —C(O)—, —C(S)—, —C(R)₂—, —CH(R)—, —C(F)₂—, —N(R)—, —S(O)₂— or—(C)═CH—; and m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,or
 16. 10. The compound of claim 9, wherein said compound is a compoundof formula I-a-13:

or a pharmaceutically acceptable salt thereof.
 11. The compound of claim3, wherein LBM is a cereblon E3 ubiquitin ligase binding moiety offormula I-nn:

or a pharmaceutically acceptable salt thereof, wherein: Ring E isselected from

each of X¹, X⁶, and X⁷ is independently a bivalent moiety selected froma covalent bond, —CH₂—, —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—,—P(O)NR₂—, —C(O)—, —C(S)—, and

each of X³ and X⁵ is independently a bivalent moiety selected from acovalent bond, —CR₂—, —NR—, —O—, —S—, and SiR₇; X⁴ is a trivalent moietyselected from

each R is independently hydrogen, or an optionally substituted groupselected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated orpartially unsaturated heterocyclic having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, and a 5-6 memberedheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen aretaken together with their intervening atoms to form a 4-7 memberedsaturated, partially unsaturated, or heteroaryl ring having 0-3heteroatoms, in addition to the nitrogen, independently selected fromnitrogen, oxygen, and sulfur; each R^(3a) is independently hydrogen,deuterium, —R⁶, halogen, —CN, —NO₂, —OR, —SR, —NR₂, —SiR₃, —S(O)₂R,—S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR,—C(R)₂N(R)C(O)R, —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂,—OP(O)(OR)₂, —OP(O)(OR)NR₂, —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,—N(R)C(O)NR₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂, —N(R)P(O)(OR)NR₂,—N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R; each R⁶ is independently an optionallysubstituted group selected from C₁₋₆ aliphatic, phenyl, a 4-7 memberedsaturated or partially unsaturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur,and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur; each R⁷ is independentlyhydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R, —NR₂,—P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)R₂, —Si(OH)₂R, —SiR₃, oran optionally substituted C₁₋₄ aliphatic; or R⁷ and X¹ or X³ are takentogether with their intervening atoms to form a 5-7 membered saturated,partially unsaturated, carbocyclic ring or heterocyclic ring having 1-3heteroatoms, independently selected from boron, nitrogen, oxygen,silicon, or sulfur; two R⁷ groups on the same carbon are optionallytaken together with their intervening atoms to form a 3-6 membered spirofused ring or a 4-7 membered heterocyclic ring having 1-2 heteroatomsindependently selected from boron, nitrogen, oxygen, silicon, andsulfur; two R⁷ groups on adjacent carbon atoms are optionally takentogether with their intervening atoms to form a 3-7 membered saturated,partially unsaturated, carbocyclic ring or heterocyclic ring having 1-3heteroatoms independently selected from boron, nitrogen, oxygen,silicon, and sulfur, or a 7-13 membered saturated, partiallyunsaturated, bridged heterocyclic ring, or a spiro heterocyclic ringhaving 1-3 heteroatoms, independently selected from boron, nitrogen,oxygen, silicon, and sulfur; Ring D is selected from 6 to 10-memberedaryl or heteroaryl containing 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, 5 to 7-membered saturated orpartially unsaturated carbocyclyl, 5 to 7-membered saturated orpartially unsaturated heterocyclyl with 1-3 heteroatoms independentlyselected from boron, nitrogen, oxygen, silicon, and sulfur, and5-membered heteroaryl with 1-4 heteroatoms independently selected fromnitrogen, oxygen and sulfur; L¹ is a covalent bond or a C₁₋₃ bivalentstraight or branched saturated or unsaturated hydrocarbon chain wherein1-2 methylene units of the chain are independently and optionallyreplaced with —O—, —C(O)—, —C(S)—, —C(R)₂—, —CH(R)—, —C(F)₂—, —N(R)—,—S—, —S(O)₂— or —(C)═CH—; n is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or4.
 12. The compound of claim 11, wherein said compound is a compoundselected from any one of the following formulae:

or a pharmaceutically acceptable salt thereof. 13-22. (canceled)
 23. Thecompound according to claim 1, wherein L is a covalent bond or abivalent, saturated or unsaturated, straight or branched C₁₋₂₀hydrocarbon chain, wherein 0-6 methylene units of L are independentlyreplaced by -Cy-, —O—, —N(R)—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—,—S(O)₂—, —N(R)S(O)₂—, —S(O)₂N(R)—, —N(R)C(O)—, —C(O)N(R)—, —OC(O)N(R)—,—N(R)C(O)O—;
 24. The compound of claim 1, wherein said compound isselected from any one of the compounds depicted in Table 1, or apharmaceutically acceptable salt thereof.
 25. A pharmaceuticalcomposition comprising a compound of claim 1, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.
 26. The pharmaceuticalcomposition according to claim 25, further comprising an additionaltherapeutic agent.
 27. A method of degrading IRAK4 protein kinase in apatient or biological sample comprising administering to said patient,or contacting said biological sample with a compound of claim 1, or apharmaceutical composition thereof.
 28. A method of treating anIRAK4-mediated disorder, disease, or condition in a patient comprisingadministering to said patient a compound of claim 1, or a pharmaceuticalcomposition thereof.
 29. The method according to claim 28, furthercomprising administration of an additional therapeutic agent.
 30. Themethod according to claim 28, wherein the IRAK4-mediated disorder,disease or condition is an inflammatory disorder.
 31. The methodaccording to claim 30, wherein the inflammatory disorder is selectedfrom the group consisting of ocular allergy, conjunctivitis,keratoconjunctivitis sicca, vernal conjunctivitis; allergic rhinitis,hemolytic anemia, aplastic anemia, pure red cell anemia, idiopathicthrombocytopenia or another inflammatory disease in which autoimmunereactions are implicated or which have an autoimmune component oretiology, systemic lupus erythematosus, rheumatoid arthritis,polychondritis, scleroderma, Wegener granulamatosis, dermatomyositis,chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome,idiopathic sprue, ulcerative colitis, Crohn's disease or anotherautoimmune inflammatory bowel disease, irritable bowel syndrome, celiacdisease, periodontitis, hyaline membrane disease, kidney disease,glomerular disease, alcoholic liver disease, endocrine opthalmopathy,Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivitypneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis(anterior and posterior), Sjogren's syndrome, vernalkeratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis,systemic juvenile idiopathic arthritis, nephritis, diverticulitis,interstitial cystitis, glomerulonephritis (with and without nephroticsyndrome, optionally including idiopathic nephrotic syndrome or minalchange nephropathy), chronic granulomatous disease, endometriosis,leptospiriosis renal disease, glaucoma, retinal disease, aging,headache, pain, complex regional pain syndrome, cardiac hypertrophy,muscle wasting, catabolic disorders, obesity, fetal growth retardation,hyperchlolesterolemia, heart disease, chronic heart failure,mesothelioma, anhidrotic ecodermal dysplasia, Behcet's disease,incontinentia pigmenti, Paget's disease, pancreatitis, hereditaryperiodic fever syndrome, asthma (allergic, non-allergic, mild, moderate,severe, bronchitic, or exercise-induced), acute lung injury, acuterespiratory distress syndrome, eosinophilia, hypersensitivities,anaphylaxis, nasal sinusitis, silica induced diseases, COPD (reductionof damage, airways inflammation, bronchial hyperreactivity, remodelingor disease progression), pulmonary disease, cystic fibrosis,acid-induced lung injury, pulmonary hypertension, polyneuropathy,cataracts, muscle inflammation in conjunction with systemic sclerosis,inclusion body myositis, myasthenia gravis, thyroiditis, Addison'sdisease, lichen planus, Type 1 diabetes, Type 2 diabetes, appendicitis,atopic dermatitis, allergy, blepharitis, bronchiolitis, bronchitis,bursitis, cervicitis, cholangitis, cholecystitis, chronic graftrejection, colitis, conjunctivitis, cystitis, dacryoadenitis,dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis,enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis,fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura,hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy,interstitial lung disease, laryngitis, mastitis, meningitis, myelitismyocarditis, myositis, nephritis, oophoritis, orchitis, osteitis,otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonia, polymyositis, proctitis, prostatitis,pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis,tendonitis, tonsillitis, vaginitis, vasculitis, vulvitis, alopeciaareata, erythema multiforma, dermatitis herpetiformis, scleroderma,vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid,pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus,epidermolysis bullosa acquisita, acute and chronic gout, chronic goutyarthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis,juvenile rheumatoid arthritis, cryopyrin associated periodic syndrome(CAPS), and osteoarthritis.